The neuroprotective effects of cholecystokinin in the brain: antioxidant, anti-inflammatory, cognition, and synaptic plasticity

Hailiang Cui; Zhonghua Li; Hongyu Sun; Wanlin Zhao; He Ma; Li Hao; Zhenqiang Zhang; Christian Hölscher; Dongrui Ma; Zijuan Zhang

doi:10.1515/revneuro-2024-0142

Article Publicly Available

The neuroprotective effects of cholecystokinin in the brain: antioxidant, anti-inflammatory, cognition, and synaptic plasticity

Hailiang Cui , Zhonghua Li , Hongyu Sun , Wanlin Zhao , He Ma , Li Hao , Zhenqiang Zhang , Christian Hölscher , Dongrui Ma and Zijuan Zhang

Published/Copyright: January 21, 2025

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From the journal Reviews in the Neurosciences Volume 36 Issue 4

Abstract

Cholecystokinin (CCK) is a major neuropeptide in the brain that functions as a neurotransmitter, hormone, and growth factor. The peptide and its receptors are widely expressed in the brain. CCK signaling modulates synaptic plasticity and can improve or impair memory formation, depending on the brain areas studies and the receptor subtype activated. Studies have shown in a series of animal models of neurodegenerative diseases that CCK receptor agonists show neuroprotective effects and can effectively alleviate oxidative stress, alleviate chronic inflammation of the central nervous system, improve neuronal synaptic plasticity, prevent neuronal loss, and improve cognitive dysfunction in Alzheimer’s disease (AD) model mice and motor activity in animal models of Parkinson’s disease. In addition, CCK plays important roles in the amygdala to regulate anxiety and depressive states. Activation of interneurons or inhibition of excitatory neurons can improve anxiety levels. This review summarizes the effects on memory formation and synaptic plasticity, the neuroprotective effects of cholecystokinin and its analogs in neurological diseases such as Alzheimer and Parkinson’s disease, and the effects on anxiety and neuronal activity in the amygdala.

Keywords: cholecystokinin; neuroprotection; chronic inflammation; synaptic plasticity; oxidative stress

1 Introduction

Cholecystokinin (CCK) is a brain gut peptide with multiple effects, including inducing gallbladder contraction, acting as a neurotransmitter, affecting emotions, memory, sensation, and regulating digestive system metabolism (Dockray 1976). CCK exists in various molecular forms, such as CCK-58, CCK-33, CCK-8, CCK-12, CCK-39, and CCK-4 (Cantor and Rehfeld 1989). It exerts its effects by binding to its receptors, which include two highly homogeneous protein cascade receptors, CCKA receptor (CCKAR) and CCKB receptor (CCKBR) (Ding et al. 2022). CCKAR is mainly distributed in peripheral tissues, the peripheral nervous system, and brain regions such as the gastrointestinal tract, nucleus tractus solitarius, pancreas, and gallbladder (Crawley et al. 1991). In contrast, the CCKBR is mainly found in central nervous system areas, including the cortex, limbic structures, hippocampus, amygdala, substantia nigra, striatum, and parts of the gastrointestinal tract (Moran et al. 1986). CCK-containing cells in the digestive system are primarily located in the mucosa of the duodenum and jejunum. Food stimulation (especially rich in fat and protein food) will trigger the small intestinal mucosa in certain cells secrete CCK (Warrilow et al. 2022). Upon binding to the gastrointestinal nerve receptor, CCK is transmitted from the gastric vagus nerve to the brain via nerve fibers inducing satiety, reducing food intake, and promoting weight loss (Gibbs et al. 1973). Studies have shown that nutrients like propionate can promote CCK expression in the digestive system by regulating intestinal bacteria metabolism (Zhang et al. 2019). Additionally, ketogenic foods may positively regulate cognitive and motor disorders in neurodegenerative disease patients by promoting CCK release in the digestive system and nervous system (Choi et al. 2021; Paoli et al. 2015). Furthermore, CCK can inhibit gastric acid hypersecretion induced by type Ⅱ diabetes in mutant mice through CCKAR (Chen et al. 2004). In the CNS, CCK’s active component, phospho-octapeptide-cholecystokinin (CCK-8s) (Zhang et al. 2023a), primarily functions as a neurotransmitter. CCK have been shown to regulate digestion, improve blood glucose level, and promote gallbladder contraction in the digestive system (Rehfeld 2017), while exhibiting neuroprotective effect in the nervous system. These neuroprotective effects are closely related to nerve growth factor (NGF) (Manni and Lundeberg 2003). In addition, CCK can affect declarative memory formation by improving synaptic plasticity between CNS neurons (Lau et al. 2023). CCK-8 can promote maze learning and memory formation in rats (Voits et al. 2001) and in APP/PS1 mice by increasing the density and number of dendritic spines in neurons (Zhang et al. 2013). Recent studies have found that inhibiting cholecystokinin-expressing interneurons (CCKIs) in the CA1 region can enhance contextual memory under certain conditions (Rangel Guerrero et al. 2024). Moreover, factors such as mitophagy (Sun et al. 2015), mitochondrial DNA (mt DNA) mutations (Khaidakov et al. 2003), and respiratory chain activity can affect neurodegenerative disease processes (Preston et al. 2008), including neuronal loss. Mitochondria can also regulate nervous system lesions by triggering oxidative stress and inflammation (Bratic and Larsson 2013; Harman 1956). Recent studies have found that CCK can reduce neuronal loss by regulating mitophagy, improving mitochondrial dynamics, and reducing neuroinflammation, thus playing a neuroprotective role (Hao et al. 2024).

There is a perspective that Alzheimer’s disease (AD) and Parkinson’s disease (PD) are a type of diabetes due to marked insulin resistance (IR), low glucose metabolism rate, and growth factor desensitization observed in some neurodegenerative disease patients (Harman 1956; Lester-Coll et al. 2006). Consequently, peptides such as glucagon-like peptide-1 (GLP-1), liraglutide, GLP receptor agonist exendin-4, and novel dual GLP-1/GIP receptor agonists (DA4-JC, DA5-CH) can effectively slow AD and PD progression, rapidly cross the BBB, and exhibit significant neuroprotective effects. Liraglutide and exendin-4 have shown promising therapeutic effects in clinical trials in PD patients (Hölscher 2022; Meissner et al. 2024). As a widely present peptide hormone in the brain, CCK has also been found to play a neuroprotective role by improving insulin resistance. CCK administration can induce insulin to cross the blood–brain barrier (BBB) and accumulate in the cerebrospinal fluid (May et al. 2016). In addition, the CCKBR expression is more widespread in the CNS. Studies have found that the neuroprotective effect of CCKBR is not limited to the hippocampus but also extends to the amygdala, hypothalamus, entorhinal cortex, and other locations by regulating synaptic plasticity (Chung and Moore 2009; Feng et al. 2021). However, the role of CCKAR in AD and PD has not been fully explored due to its limited brain expression (Table 1).

Table 1:

Structure and neuroprotective function of peptides.

Type	Structure	Neuroprotective effect	References
CCK analogs	Based on the basic structure of CCK, modified the peptide fragment to increase its stability and prolong its half-life in vivo	Activate CCKBR in CA1 region of hippocampus. Enhancing synaptic plasticity, regulating mitochondrial dynamics, reducing amyloid plaque deposition, and inhibiting inflammation and apoptosis	(Hao et al. 2024; Reich and Holscher 2024)
CCK-8	A 33-amino acid polypeptide and CCK-8 is the most abundant in the brain	Acts by binding to CCKAR and CCKBR receptors. Involved in regulating the release of dopamine and hippocampal glutamate and controlling the activity of GABAergic basket cells, thereby improving the acquisition of declarative memory. Induces the synthesis of nerve growth factor and BDNF, and regulates the expression TrkB in the hippocampus. Antineuroinflammation and inhibition of apoptosis	(Reich and Holscher 2024; Tirassa and Costa 2007)
GLP-1	A peptide hormone of 31 amino acids.	Acts by binding to the GLP-1 receptor. Cross the BBB, protect synapses, attenuate apoptosis, protect neurons from oxidative stress, and protect memory formation. Mediates changes in glucose metabolism, enhances glycolytic flow, and reduces mitochondrial ROS level, thereby enhancing the ability of astrocytes to support neurons. Reduce the production of inflammatory cytokines and immune cell infiltration, enhancing neurovascular coupling to promote neuronal regeneration and functional recovery	(Müller et al. 2019; Reich and Hölscher 2022)
Liraglutide	A GLP-1 analog with the Lys26 side chain of liraglutide coupled to a C-16 fatty acid linked by a glutamic acid spacer. This palmitic acid modification prolongs its half-life in vivo	Acts by binding to the GLP-1 receptor. Reduce learning and memory impairment, improve synaptic plasticity, reduce oxidative stress and inflammation, inhibit neuronal apoptosis, and reduce hippocampal neuron loss. Reduces β-amyloid oligomer levels and tau hyperphosphorylation, and promotes neurogenesis	(Knudsen and Lau 2019; Reich and Hölscher 2022)
Exendin-4	A 39-amino acid polypeptide with about 53 % sequence identity with mammalian GLP-1 in the first 30 amino acid residues. The C-terminus is extended by nine amino acids. The C-terminal extension supports the secondary structure by forming a “tryptophan cage” and increases the potency of the GLP-1 receptor	As a GLP-1 receptor agonist, it can significantly reduce the loss of dopaminergic neurons and the accumulation of α-synuclein in the parkinsonian brain, reduce mitochondrial toxicity and the expression of proinflammatory mediators, and improve the firing activity of hippocampal CA1 neurons in rats. Improving cognitive function. The specific binding of GLP-1 receptor on the membrane of islet β cells can activate the cAMP/PKA signal transduction pathway, inhibit endoplasmic reticulum related cell apoptosis, and protect nerve damage induced by high glucose. Promotes the proliferation and migration of Schwann cells, thereby improving the ability of nerve regeneration and protecting against high glucose-induced nerve injury.	(Li et al. 2009; Neidigh et al. 2001; Pandey et al. 2023)
DA4-JC	A GLP-1/GIP dual receptor agonist	Acts by binding to GLP-1 and GIP receptors. Improve cognitive function, protect the plasticity of hippocampal synapses, increase the number of dendritic spines of hippocampal neurons, and increase the levels of hippocampal PSD95 and SYP proteins. Reduce the deposition of Aβ and p-tau protein in the brain. The mitochondrial autophagy pathway was improved, and the levels of PINK1 and Parkin were up-regulated. Enhanced hippocampal long-term potentiation (LTP)	(Cai et al. 2021; Maskery et al. 2020)
DA5-CH	A novel dual agonist of GLP-1/GIP that can cross the BBB faster than semalutide.	Activated GLP-1 and GIP receptors. Improved working memory and long-term spatial memory, and reduced the level of phosphorylated tau protein in the hippocampus; Reduced the death of dopaminergic neurons in the substantia nigra of mice, increased the number of surviving neurons, and decreased the level of α-synuclein. Increased the activity energy of theta band in hippocampal CA1 region, improved the expression of synapse-associated proteins, and alleviated mitochondrial stress. Prevented the excessive activation of p-GSK3β and increased the level of transcription factor P-CREB-S133. Inhibition of neuroinflammation.	(Cao et al. 2018; Li et al. 2020; L. Zhang et al. 2022; Z. Zhang et al. 2022)

2 Possible mechanisms of the neuroprotective effect of cholecystokinin

A growing number of studies have demonstrated the neuroprotective effects of CCK in the CNS. The results of animal studies also support the protective effect of CCK on CNS neurons. However, the study of the neuroprotective role of CCK in the CNS is unclear. It has been shown that CCK is involved in regulating synaptic plasticity in a variety of neuronal subtypes in the CNS (Chung and Moore 2009). In this section, we will explore the neuroprotective effects of CCK exhibited by regulating neuroinflammation, restoring synaptic plasticity, ameliorating mitochondrial dysfunction, and modulating oxidative stress.

2.1 CCK and synaptic plasticity

The synapse is a crucial structure for mediating neuronal connections and signal communication. It consists of presynaptic axon terminals, the synaptic cleft, and postsynaptic terminals, transmitting information to the next level through electrical and chemical signals. Synaptic plasticity is essential in forming neural circuits and is closely related to learning and memory (Zhang et al. 2023b). Synaptic plasticity can be divided into early and late stages. The early stage regulates neurotransmitter release, while the late stage produces lasting changes in synaptic transmission through gene expression and new protein synthesis. CCK functions as a neurotransmitter in the mammalian central nervous system, and its abnormality can lead to neuronal dysfunction or death (Zhang et al. 2023a). The analysis of cerebrospinal fluid (CSF) of AD patients have found that high levels of CCK expression in the brain is inversely correlated with memory impairment and brain damage in AD patients (Plagman et al. 2019). Long-term potentiation (LTP) is a form of synaptic plasticity. Studies have found that cholecystokinin sulfated octapeptide (CCK-8s) can improve LTP impairment and spatial memory impairment in the hippocampal CA1 region of rats and can increase the density of dendritic spines of hippocampal neurons via CCKBR (Gronier and Debonnel 1995). CCK has been found to modulate pyramidal neurons in the CA1 and CA3 regions of the hippocampus and regulate GABAergic release (Boden and Hill 1988; Gronier and Debonnel 1995; Karson et al. 2008). Electrical stimulation of the molecular layer of the dentate gyrus in mouse hippocampal slices or the CA1 and CA3 regions can induce AMPA receptor-mediated excitatory postsynaptic currents (EPSCs), increasing the amount of vesicle release and the number of vesicles, inducing glutamate release (Deng et al. 2010). Recent studies have found that specific binding of CCK to GPR173, a novel CCK receptor on the postsynaptic membrane, in the auditory cortex can promote inhibitory long-term potentiation (iLTP) by regulating glutamate – and γ-aminobutyric acid (GABA) – mediated synaptic transmission. Meanwhile, GABAergic CCK + neurons may induce heterosynaptic LTP, leading to enhanced postsynaptic potentials (Asim et al. 2024a). Endogenous CCK can promote the aggregation of G protein-coupled receptors through CCKBR activation, leading to increased glutamate release (Deng et al. 2010). Administration of CCK-8S has been shown to increase synaptosomal protein and postsynaptic density protein 95 (PSD-95), enhancing spatial learning and memory of mice in the water maze and Y maze tasks (Zhang et al. 2023b). A single theta pulse at the Schaffer collateral and pathway induces LTP and NMDA receptor activation, which are closely associated with LTP induction (Dolatabadi and Reisi 2014). CCK-8S treatment was found to prolong the fEPSP slope and PS amplitude, enhancing LTP in the hippocampal CA1 region (Dolatabadi and Reisi 2014). Additionally, CCK-8S could regulate the excitability of hippocampal CA1 neurons by regulating K⁺ and Ca²⁺ in hippocampal CA1 neurons (Shinohara and Kawasaki 1997). Since CCK + positive neurons are closely related to CCK, CCK can promote the excitatory transmission by mediating the firing frequency of CCK + positive neurons (Böhme et al. 1988). Another empirical study also demonstrated that peripherally administered CCK-8S and cholecystokinin-fragments Boc-CCK-4 enhanced habituation to novel environmental stimuli immediately after the trial and induced enhanced memory consolidation (Gerhardt et al. 1994). Moreover, CCK fragments may dose-dependently enhance or attenuate memory, reinforcement effect, and anxiety behavior by affecting the activity of the amygdala region (Huston et al. 1998). Neurotrophic factors in the brain possess neuroprotective effects, and their decreased conduction is one of the hallmarks of neurodegenerative diseases (Hölscher 2022). Studies have found that brain-derived neurotrophic factor (BDNF) injection in the brains of AD mice can increase BDNF level in hippocampal synapses, improve synaptic loss, and enhance LTP (Blurton-Jones et al. 2009). A recent study found that the binding of CCK to the postsynaptic membrane CCKBR can activate the RAS-Raf-MAPK pathway to enhance the formation of LTP in the hippocampus and promote the release of BDNF to regulate synaptic plasticity and exert neuroprotection (Asim et al. 2024a). These findings suggest that CCK may regulate synaptic plasticity and protect neurons by improving LTP, increasing the presynaptic membrane thickness, promoting synaptic vesicle release, and boosting the excitability of CCK neurons (Figure 1). In different brain areas, CCK signaling can induce very different effects. In the hippocampus, the main effect will be modulation of memory formation, while in the amygdala, activation of GABAergic interneurons that express CCK modulate anxiety and depression-like states, in context with the activity of parvalbumin-expressing interneurons (Asim et al. 2024b). Importantly, CCKBR activation in the basolateral amygdala can induce LTP that supports anxiety memories. Hence, blocking CCKBRs can have antianxiety like effects, while activating GABAergic inhibitory interneurons can have antianxiety effects, too (Zhang et al. 2023c).

Figure 1:

CCK and synaptic plasticity. The binding of CCK to its receptor CCKBR can promote the release of glutamate at the presynaptic membrane and postsynaptic density protein 95 (PSD-95) and induce the enhancement of LTP at the postsynaptic membrane. The binding of CCK to the postsynaptic membrane CCKBRs promotes the production of brain-derived neurotrophic factor (BDNF) and neuroprotection.

2.2 CCK and neuroinflammation

One of the key factors in neurodegenerative diseases is chronic inflammation (Mou et al. 2022). The pathological manifestations of AD include amyloid β protein (Aβ) deposition, leading to the formation of extracellular inflammatory plaques (Jorfi et al. 2023; Wang et al. 2023). Chronic brain inflammation is also a key factor in the pathogenesis of PD and can be exacerbated by diabetes (Cheong et al. 2020). Autopsy data have shown significant numbers of activated microglia and inflammatory factors near necrotic neurons in the brain of AD patients and around the lesions in the brain of PD patients (Cheong et al. 2020). Microglia are the main immune cells in the CNS, responding first to antigens and releasing inflammatory factors such as IL-6, IL-10, and tumor necrosis factor α (TNF-α) (Magni et al. 2012). In the early stage of AD and PD, moderately activated microglia help to protect neurons. However, as the disease progresses, inflammatory factors activate microglia (Blandini 2013), and overactivated microglia release cytotoxic factors, exacerbating neuronal damage (Xu et al. 2016). CCK has been reported to control macrophages activation through CCKAR, NF-κB, and CAMP-PKA pathways, exerting anti-inflammatory effects (Saia et al. 2014). Studies have shown that CCK-8 can inhibit methamphetamine (METH)-induced microglial activation and neuroinflammation by down-regulating the NF-κB signaling pathway via CCKBR (Gou H et al. 2020). In addition, intraperitoneal injection of CCK analog significantly reduce the expression of microglia marker IBA-1 and astrocyte marker GFAP in SNpc of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) – induced PD mouse model, reduced the expression of inflammatory factor IL-1β, and exhibited neuroprotective effect (L. Zhang et al. 2022; Z. Zhang et al. 2022). Furthermore, administration of CCK analogs and liraglutide reduced colonic inflammation in PD mouse models, reducing inflammatory biomarkers expression such as inducible nitric oxide synthase (iNOS) and tumor necrosis factor α (TNF-α), and improved the colonic pathology in PD patients (Su et al. 2022). These findings suggest that the use of CCK or its analogs may have neuroprotective effects in preventing and alleviating inflammatory damage in neurodegenerative diseases such as AD and PD (Figure 2).

Figure 2:

CCK and neuroinflammation. CCK can bind to its receptor CCKBR and activate its subunits to inhibit the NF-κB pathway to release inflammatory factors and reduce neuronal death.

2.3 CCK and mitochondrial damage

Mitochondria are critical organelles in eukaryotic cells, especially for neurons’ synaptic terminals, which rely heavily on the energy produced by mitochondria (de Castro IP et al. 2011). Some researchers speculate that mitochondrial dysfunction is closely related to the process of neurodegenerative diseases (Klemmensen et al. 2024), dysfunction of mitochondria may trigger neuronal defects, leading to neuronal death even before early synapse formation (Saia et al. 2014). Studies have found defects in glucose utilization in the early stage of AD, in which Aβ can inhibit mitochondrial energy production by inhibiting several mitochondrial enzymes, thereby destroying mitochondrial function (Keil et al. 2004). Electron microscopy showed that the brain mitochondria in AD patients showed typical symptoms such as volume reduction, cristae fracture, and accumulation of osmotic substances (Zhang et al. 2016). Tau protein neuronal tangles, a pathological feature of AD (Wegmann et al. 2021), and abnormal Tau protein can lead to mitochondrial dysfunction, which has also been found in AD and PD mouse models (David et al. 2005). A recent study found that abnormal mitochondrial dynamics was associated with AD, mainly manifested by neuronal Aβ oligomers aggregation, leading to mitochondrial dysfunction, inducing neurotoxicity, and ultimately causing neuronal damage (Calkins et al. 2011). The pathogenesis of PD is also closely related to mitochondrial dysfunction (Rango and Bresolin 2018). Mitochondria generate energy through the molecular mechanism of electron transport chain (ETC). In the process of electron transport, a large amount of superoxide is produced (Schapira et al. 1989), enhancing the oxidative stress in dopaminergic neurons, leading to the loss of neurons in the substantia nigra region of PD patients (Mattson et al. 2008). AMPK plays a crucial role in regulating mitochondrial dynamics (J. Li et al. 2015; Y. Li et al. 2015), and it can be directly activated by small molecule activators. AMPK can inhibit Drp1 activity by phosphorylating the Ser637 site of mitochondrial fission factor (MFF), thus inhibiting abnormal division and regulating the balance of mitochondrial dynamics (Kim et al. 2020). Recent studies have found that a novel CCK-8 analog can activate CCKBR in the hippocampal CA1 region and regulate mitochondrial damage in APP/PS1 mice through the AMPK/Drp1 pathway, alleviating the abnormal reduction of mitochondrial fusion protein mitofusin 2 (Mfn 2) and optic atrophy 1 (OPA 1), thereby balancing mitochondrial dynamics and improving cognitive impairment in AD mice (Hao et al. 2024). It was also found that both CCK analog and liraglutide could effectively improve mitochondrial morphological changes, reduce synaptic loss, and significantly inhibit mitochondrial damage in the MPTP-induced PD mouse model (L. Zhang et al. 2022; Z. Zhang et al. 2022). While many studies have shown the role of mitochondria in neurodegenerative diseases, there are still controversial issues requiring further research (Monzio Compagnoni et al. 2020). The improvement of mitochondrial dynamics and dysfunction with CCK analogs may lead to new therapeutic approaches for the research and treatment of neurodegenerative diseases (Figure 3).

Figure 3:

CCK and mitochondrial damage. CCK can promote the production of AMPK by binding to its receptor, and AMPK can phosphorylate the Ser637 site on MFF to reduce the activity of Drp1 and reduce mitochondrial fission.

2.4 CCK and oxidative stress

The CNS is one of the most metabolically active organs in humans, requiring large amounts of oxygen. The oxygen molecules damage produces a large number of reactive oxygen species (ROS), and the free radicals produced by reactive oxygen species are closely related to synaptic plasticity, cell function, aging, and apoptosis (Elfawy and Das 2019). Oxidative stress (OS) is closely linked to aging and can directly damage the central nervous system (Simpson and Oliver 2020). ROS produce cytotoxic compounds that cause protease failure and neuronal cell death. NADPH oxidase (NOX) plays an important role in producing ROS within neurons, which can induce OS and neurotoxicity (Ferrucci et al. 2008). The generation of ROS is also closely related to mitochondria, with superoxide radicals being particularly significant (Dong-Chen et al. 2023). Superoxide free radicals produced by the electron transport cascade can be converted to hydrogen peroxide by superoxide dismutase Ⅱ, which inhibit oxidative stress damage caused by continuous high ROS concentration. OS can lead to mitochondrial protein damage and mitochondrial dysfunction (Dong-Chen et al. 2023). Oxidative stress can damage pyramidal cells in the CA3 region of the hippocampus and granule cells in the DG region, leading to neuronal dysfunction (Esmaeili et al. 2022). OS is also associated with the development of neuroinflammation. ROS can activate astrocyte-mediated inflammation and cause the release of inflammation-related factors (Dong-Chen et al. 2023; El-Kenawi and Ruffell 2017). Excessive release of inflammatory factors leads to neuronal damage. CCK-8 can prevent retinal pigment epithelium (RPE) OS-induced cell damage by regulating caspase-8 signaling and reduce oxidative stress and nerve damage caused by METH abuse by binding to CCKBR isoforms (Wen et al. 2016). Studies have found that CCK-8 can inhibit the “waterfall effect” of LPS and ROS, reducing oxidative damage (Su et al. 2013). Glucagon-like peptide-1 (GLP-1) and CCK are brain-gut peptides that can inhibit appetite by regulating the central system and have shown good neuroprotective effects. Studies have found that GLP-1 and its analogs also alleviate neuronal damage after cerebral ischemia in rats by blocking apoptosis and reducing oxidative stress (J. Li et al. 2015; Y. Li et al. 2015). These results indicate that CCK is also effective in preventing oxidative stress and protecting neurons (Figure 4).

Figure 4:

CCK and oxidative stress. Mitochondrial damage caused by aging, genetic damage, stress, and other factors leads to increased production of reactive oxygen species, stimulating the activation of glial cells, releasing inflammatory factors, and causing neuronal death.

3 CCK and disease

3.1 CCK and Alzheimer’s disease

The main pathological manifestation of AD is neuron loss (Mantzavinos and Alexiou 2017), and neuronal death leads to permanent disruption of neural circuit connections. This disruption affects memory recall and interferes with the brain’s cognitive and sensory information processing, resulting in memory decline and cognitive impairment (Lau et al. 2023). AD is closely related to aging, and the content of CCK and its receptors in the brain also decreases significantly with aging. CCK expression was found to be decreased in aged rats with cognitive impairment (Zhang et al. 2023c). Type 2 diabetes mellitus (T2DM) is also a significant factor in AD pathogenesis (Hölscher 2019). Insulin resistance in the brain of AD patients results in slow glucose metabolism and damage to glucose metabolism-related enzymes (Hölscher 2019). Animal experiments have found that CCK can promote incretin production and subsequently the release of insulin (Hölscher 2019). In addition, CCK may serve as a biomarker for AD-related learning and memory abilities. Studies have found that the loss of CCK induces cognitive impairments in mice (Lo et al. 2008). In vitro studies have shown that CCK knockout (CCK–KO) mice show a significant decline in spatial memory ability during water maze task compared to wild type (WT) mice (Lo et al. 2008). Intraperitoneal injection of CCK analog can prolong the escape latency in water maze tests in APP/PS1 mice (Zhang et al. 2023b). To further determine the neuroprotective effects of CCK analogs in AAP/PS1 mice, studies developed an APP/PS1 transgenic mouse model with Cas9 targeted knockout of CCKBR in the hippocampal CA1 region. Y-maze tests showed that the spontaneous alternation of the CCK-8 group was more than that of the APP/PS1 group. Water maze tests showed that the escape latency of the CCK-8 treatment group was significantly shorter than that of the APP/PS1 (+) group (Hao et al. 2024). These results suggest that CCK analogs can improve working and spatial memory in APP/PS1 mouse models. It was also found that CCK-8S administration in 1-day-old primary cultures of neurons from wild-type or APP/PS1 mice increased the number of dendritic spines and dendritic pseudopodia in hippocampal neurons from APP/PSI mice and wild-type mice (Liu et al. 2021). In addition, CCK administration was found to promote excitatory synaptic transmission and reduce synaptic depression (Zhang et al. 2023b). These results indicate that CCK could effectively improve neuronal damage and enhance memory formation in AD mice.

3.2 CCK and Parkinson’s disease

PD is the second most common neurodegenerative disease (Monzio Compagnoni et al. 2020), characterized by the degeneration and death of dopaminergic neurons in the substantia nigra, with decreased of striatal dopamine (DA) and abnormal deposition of α-synuclein (α-syn) (Poewe et al. 2017). The onset of PD is also associated with T2DM (Hassan et al. 2020). The decreased expression of glucose metabolism enzymes in PD patient brain leads to reduced glucose metabolism and dysregulation of the downstream pathway of insulin receptors in the dorsal substantia nigra pars compacta (SNpc) (Hölscher 2019). CCK has been found to colocalize with DA in cortical neurons of the ventral midbrain (Seroogy et al. 1989). The neuronal population affected in PD is predominantly in the substantia nigra, where CCK receptors are also found on dopaminergic neurons (Fallon and Seroogy 1985). Several studies have shown that brain-gut peptides such as CCK, GLP-1, and liraglutide can effectively ameliorate neuronal loss in PD mice (Zhang and Holscher 2020). CCK analogs have been found to have a good neuroprotective effect on MPTP-induced mice (L. Zhang et al. 2022; Z. Zhang et al. 2022). These drugs reduced motor impairment and loss of TH expression in the substantia nigra and downregulated MPTP-induced phosphorylation of cAMP response element-binding protein (CREB) (Zhang Z et al. 2022). The dopamine one receptor (D1R) in SNpc is decreased in the 6-hydroxydopamine (6-OHDA)-induced rat PD model (Nilsson et al. 2009). Studies have found that CCK-8S can improve motor performance by stimulating dopamine release (You et al. 1996). At the same time, studies have found that the neuropeptide Substance-P (SP) and CCK fragment Boc-CCK-4 can play a neuroprotective role by improving on the 6-OHDA-induced nigrostriatal damage and enhancing the expression of dopamine (Nikolaus et al. 1999). Chronic inflammation is also a key factor in the pathogenesis of PD. Previous studies have found that CCK analogs reduce IL-1β expression in MPTP-induced PD mouse models (L. Zhang et al. 2022; Z. Zhang et al. 2022). Constipation is one of the most common gastrointestinal symptoms in PD patients (Fasano et al. 2015). The change of intestinal permeability in the early stage of PD is related to the change of intestinal α-syn levels (Kim et al. 2019), and CCK can increase the BDNF release in the intestinal system, playing a neuroprotective role (Su et al. 2022). A recent study found that subcutaneous injection of a CCK analog or liraglutide reduced intestinal inflammation and regulated dopamine neurons and α-syn accumulation in the chronic MPTP-induced PD mouse model and the human A53T α-syn transgenic PD mouse model (Su et al. 2022). Additionally, it was found that the novel CCK analog had a high BBB crossing rate (L. Zhang et al. 2022; Z. Zhang et al. 2022). These results suggest that CCK can effectively ameliorate neuronal damage and alleviate the clinical symptoms in PD mice.

3.3 CCK and pain

CCK, as a brain-gut peptide, plays a central regulator role in the nervous system. The regulatory regions of pain in CNS include the cerebral cortex, gray matter, hypothalamus, midbrain periaqueductal gray (PAG), ventromedial thalamus, and spinal dorsal horn (Baber et al. 1989). CCK is also expressed in these areas, with high expression in the cerebral cortex and gray matter (Baber et al. 1989). Caerulein, a gastric regulatory molecule similar in function and composition to CCK, shares a C-terminal amino acid sequence with CCK. Caerulein works with CCK to regulate pain perception in the CNS (Price et al. 1985). Intravenous injection of caerulein in humans can relieve acute biliary colic and renal colic (Price et al. 1985). The periaqueductal gray matter (PAG) is a key region for endogenous pain regulation. PAG and periventricular neurons send information along the dorsolateral funiculus (DLF) to the substantia gelatinosa (SG) in the dorsal horn of the spinal cord. High concentrations of CCK can regulate enkephalinergic interneurons to reduce pain (McRoberts 1986). Proglumide, a peripheral competitive specific receptor of CCK, can enhance the analgesic effect of morphine (Price et al. 1985). Intrathecal injection of proglumide at low dose can enhance the analgesic effect induced by forepaw paw click in rats, while high dose have the opposite effect (Zetler 1980). This study found that subcutaneous injection of CCK had short-term sedative and analgesic effects and blepharoptosis in mice, while CCK-8 injection into the PAG of rats had a more pronounced effect than morphine (Zetler 1980). Additionally, besides its own analgesic effect, CCK-8 can enhance the analgesic effect of opioids and reduce the pain sensitivity of organisms. The analgesic effect of CCK-8 may also be related to its efficacy as a neurotransmitter (Zetler 1980); the depolarization of CCK can promote the release of calcium and further promote neural firing. These results indicate that CCK-8 has a good endogenous analgesic effect, and the development of this drug may reduce the dose-dependent effect of morphine and other drugs. The evidence that CCK acts as a neurotransmitter also suggests great promise for studying the analgesic efficacy of CCK drugs.

4 Therapeutic prospects of novel CCK analogs

CCK has shown promising therapeutic effects as a neuropeptide in animal models. However, its short blood half-life and low BBB crossing rate limit its application. The short half-life of CCK in the blood and the low permeability of the BBB are due to the presence of various enzymes that degrade CCK in the blood (Hoffmann et al. 1993). Studies have found that the degradation rate of CCK in the blood can be reduced by the N-terminal modification of CCK or polyethylene glycol modification (Verbaeys et al. 2009). Consequently, newly synthesized CCK analogs have been developed that have a longer half-life in the blood and can quickly cross the BBB, playing a neuroprotective role in the central nervous system. As CCK signaling plays many roles in the brain, there is potential for developing effective drugs to address key issues such as tackling neurodegeneration in Alzheimer and Parkinson’s disease, or treating depressive disorders. The challenge is to develop selective drugs that do not broadly activate receptors in all brain regions but that are selective for specific receptors or brain systems. Delivery systems that can access specific regions or neuronal subtypes would be required to induce desired effects in the brain without affecting brain areas that are not involved in the outcome of interest. Drugs that can enter the brain and disappear from the blood faster would be more effective and show fewer side effects in the periphery. Therefore, the development of biological drugs to test the neuroprotective effects of novel CCK analogs holds broad prospect.

5 Conclusions

This review discusses the neuroprotective effects of CCK in diseases such as Alzheimer’s disease, Parkinson’s disease, and pain. A large number of experiments have demonstrated that CCK shows excellent neuroprotective effects in AD and PD mouse models. We explored the possible mechanisms by which CCK acts in the central nervous system. Existing evidence supports that CCK can prevent the damage and loss of neurons in the CNS by regulating synaptic plasticity, reducing neuroinflammation, improving mitochondrial dynamics, and regulating oxidative stress. However, its low BBB crossing rate and short blood half-life limit the neuroprotective effect of this neuropeptide. Novel CCK analogs and CCK/GLP-1 dual-receptor agonists modified by CCK gene sequence can improve the BBB crossing rate and half-life, showing good neuroprotective effects. Nonetheless, neurodegenerative diseases related to neuronal loss and apoptosis, such as Alzheimer’s disease and Parkinson’s disease, show low expression levels of CCK, and the mechanism of how CCK exerts its neuroprotective effect is still unclear. Therefore, the development of novel CCK analogs to prolong BBB transit efficiency and blood half-life of CCK, along with the neuroprotective effect of CCKAR in CNS, may be an effective strategy, bringing new hope for the treatment of neurodegenerative diseases.

Corresponding authors: Zijuan Zhang, School of Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China, E-mail: zhangzijuan2009@hactcm.edu.cn; Christian Hölscher, Henan Academy of Innovations in Medical Science, Brain Institute, Zhengzhou 451100, Henan Province, China, E-mail: c.holscher@hactcm.edu.cn; and Dongrui Ma, Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China, E-mail: dongruima@hactcm.edu.cn

Funding source: National Natural Science Foundation of China

Award Identifier / Grant number: U1504829

Funding source: Scientific and Technological Project of Henan Province

Award Identifier / Grant number: 242102311286

Funding source: Doctoral Fund of Henan University of Chinese Medicine

Award Identifier / Grant number: BSJJ2022-09

Funding source: Joint Research Fund of Science and Technology R&D Plan of Henan Province

Award Identifier / Grant number: 222301420068

Funding source: Scientific and Technological Project of Henan Province

Award Identifier / Grant number: 232102311223

Research ethics: Not applicable.
Informed consent: Not applicable.
Author contributions: Hailiang Cui drafted the original manuscript. Zhonghua Li, Hongyun Sun, Wanlin Zhao, He Ma, Li Hao, and Zhengqiang Zhang reviewed and edited the manuscript. Zijuan Zhang, DongRui Ma, and Christian Hölscher revised and approved the manuscript. All authors contributed to the manuscript’s editing, accepted responsibility for its entire content, and approved its submission.
Use of Large Language Models, AI and Machine Learning Tools: Not applicable.
Conflict of interest: All authors state no conflict of interest.
Research funding: This work was supported by the National Natural Science Foundation of China (Grant No. U1504829), Scientific and Technological Project of Henan Province (Grant No. 242102311286), Doctoral Fund of Henan University of Chinese Medicine (Grant No. BSJJ2022-09), Joint Research Fund of Science and Technology R&D Plan of Henan Province (Grant No. 222301420068), and Scientific and Technological Project of Henan Province (Grant No. 232102311223).
Data availability: Not applicable.

References

Asim, M., Wang, H., and Chen, X. (2024a). Shedding light on cholecystokinin’s role in hippocampal neuroplasticity and memory formation. Neurosci. Biobehav. Rev. 159: 105615, https://doi.org/10.1016/j.neubiorev.2024.105615.Search in Google Scholar PubMed

Asim, M., Wang, H., Waris, A., and He, J. (2024b). Basolateral amygdala parvalbumin and cholecystokinin-expressing GABAergic neurons modulate depressive and anxiety-like behaviors. Transl. Psychiatry 14: 418, https://doi.org/10.1038/s41398-024-03135-z.Search in Google Scholar PubMed PubMed Central

Baber, N.S., Dourish, C.T., and Hill, D.R. (1989). The role of CCK caerulein, and CCK antagonists in nociception. Pain 39: 307–328, https://doi.org/10.1016/0304-3959(89)90045-6.Search in Google Scholar PubMed

Blandini, F. (2013). Neural and immune mechanisms in the pathogenesis of Parkinson’s disease. J. Neuroimmune. Pharmacol. 8: 189–201, https://doi.org/10.1007/s11481-013-9435-y.Search in Google Scholar PubMed

Blurton-Jones, M., Kitazawa, M., Martinez-Coria, H., Castello, N.A., Müller, F.J., Loring, J.F., Yamasaki, T.R., Poon, W.W., Green, K.N., and LaFerla, F.M. (2009). Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc. Natl. Acad. Sci. U. S. A. 106: 13594–13599, https://doi.org/10.1073/pnas.0901402106.Search in Google Scholar PubMed PubMed Central

Boden, P.R. and Hill, R.G. (1988). Effects of cholecystokinin and pentagastrin on rat hippocampal neurones maintained in vitro. Neuropeptides 12: 95–103, https://doi.org/10.1016/0143-4179(88)90037-6.Search in Google Scholar PubMed

Böhme, G.A., Stutzmann, J.M., and Blanchard, J.C. (1988). Excitatory effects of cholecystokinin in rat hippocampus: pharmacological response compatible with ‘central’- or B-type CCK receptors. Brain res. 451: 309–318, https://doi.org/10.1016/0006-8993(88)90776-7.Search in Google Scholar PubMed

Bratic, A. and Larsson, N.G. (2013). The role of mitochondria in aging. J. Clin. Invest. 123: 951–957, https://doi.org/10.1172/jci64125.Search in Google Scholar

Cai, H.Y., Yang, D., Qiao, J., Yang, J.T., Wang, Z.J., Wu, M.N., Qi, J.S., and Holscher, C. (2021). A GLP-1/GIP dual receptor agonist DA4-JC effectively attenuates cognitive impairment and pathology in the APP/PS1/tau model of Alzheimer’s disease. J. Alz. Dis. 83: 799–818, https://doi.org/10.3233/jad-210256.Search in Google Scholar PubMed

Calkins, M.J., Manczak, M., Mao, P., Shirendeb, U., and Reddy, P.H. (2011). Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer’s disease. Human c. Gen. 20: 4515–4529, https://doi.org/10.1093/hmg/ddr381.Search in Google Scholar PubMed PubMed Central

Cantor, P. and Rehfeld, J.F. (1989). Cholecystokinin in pig plasma: release of components devoid of a bioactive COOH-terminus. Am. J. Physiol. 256: G53–G61, https://doi.org/10.1152/ajpgi.1989.256.1.g53.Search in Google Scholar PubMed

Cao, Y., Hölscher, C., Hu, M.M., Wang, T., Zhao, F., Bai, Y., Zhang, J., Wu, M.N., and Qi, J.S. (2018). DA5-CH, a novel GLP-1/GIP dual agonist, effectively ameliorates the cognitive impairments and pathology in the APP/PS1 mouse model of Alzheimer’s disease. Euro. J. Pharmacol. 827: 215–226, https://doi.org/10.1016/j.ejphar.2018.03.024.Search in Google Scholar PubMed

Chen, D., Zhao, C.M., Håkanson, R., Samuelson, L.C., Rehfeld, J.F., and Friis-Hansen, L. (2004). Altered control of gastric acid secretion in gastrin-cholecystokinin double mutant mice. Gastroent 126: 476–487, https://doi.org/10.1053/j.gastro.2003.11.012.Search in Google Scholar PubMed

Cheong, J.L.Y., de Pablo-Fernandez, E., Foltynie, T., and Noyce, A.J. (2020). The association between type 2 diabetes mellitus and Parkinson’s disease. J. Parkinsons Dis. 10: 775–789, https://doi.org/10.3233/JPD-191900.Search in Google Scholar PubMed PubMed Central

Choi, A., Hallett, M., and Ehrlich, D. (2021). Nutritional ketosis in Parkinson’s disease - a review of remaining questions and insights. Neurotherapeuticss 18: 1637–1649, https://doi.org/10.1007/s13311-021-01067-w.Search in Google Scholar PubMed PubMed Central

Chung, L. and Moore, S.D. (2009). Cholecystokinin excites interneurons in rat basolateral amygdala. J. Neurophysiol. 102: 272–284, https://doi.org/10.1152/jn.90769.2008.Search in Google Scholar PubMed

Crawley, J.N., Fiske, S.M., Durieux, C., Derrien, M., and Roques, B.P. (1991). Centrally administered cholecystokinin suppresses feeding through a peripheral-type receptor mechanism. J. Pharmacol. Exp. Ther. 257: 1076–1080.10.1016/S0022-3565(25)24778-4Search in Google Scholar

David, D.C., Hauptmann, S., Scherping, I., Schuessel, K., Keil, U., Rizzu, P., Ravid, R., Dröse, S., Brandt, U., Müller, W.E., et al.. (2005). Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J. Biol. Chem. 280: 23802–23814, https://doi.org/10.1074/jbc.m500356200.Search in Google Scholar PubMed

de Castro, I.P., Martins, L.M., and Loh, S.H. (2011). Mitochondrial quality control and Parkinson’s disease: a pathway unfolds. Molec. Neurobiol. 43: 80–86, https://doi.org/10.1007/s12035-010-8150-4.Search in Google Scholar PubMed PubMed Central

Deng, P.Y., Xiao, Z., Jha, A., Ramonet, D., Matsui, T., Leitges, M., Shin, H.S., Porter, J.E., Geiger, J.D., and Lei, S. (2010). Cholecystokinin facilitates glutamate release by increasing the number of readily releasable vesicles and releasing probability. J. Neurosci. 30: 5136–5148, https://doi.org/10.1523/jneurosci.5711-09.2010.Search in Google Scholar PubMed PubMed Central

Ding, Y., Zhang, H., Liao, Y.Y., Chen, L.N., Ji, S.Y., Qin, J., Mao, C., Shen, D.D., Lin, L., Wang, H., et al.. (2022). Structural insights into human brain-gut peptide cholecystokinin receptors. Cell discov. 8: 55, https://doi.org/10.1038/s41421-022-00420-3.Search in Google Scholar PubMed PubMed Central

Dockray, G.J. (1976). Immunochemical evidence of cholecystokinin-like peptides in brain. Nature 264: 568–570, https://doi.org/10.1038/264568a0.Search in Google Scholar PubMed

Dolatabadi, L.K. and Reisi, P. (2014). Acute effect of cholecystokinin on short-term synaptic plasticity in the rat hippocampus. Res. Pharm. Sci. 9: 331–336.Search in Google Scholar

Dong-Chen, X., Yong, C., Yang, X., Chen-Yu, S., and Li-Hua, P. (2023). Signaling pathways in Parkinson’s disease: molecular mechanisms and therapeutic interventions. Signal Transduct. Target Ther. 8: 73, https://doi.org/10.1038/s41392-023-01353-3.Search in Google Scholar PubMed PubMed Central

El-Kenawi, A. and Ruffell, B. (2017). Inflammation, ROS, and mutagenesis. Cancer cell 32: 727–729, https://doi.org/10.1016/j.ccell.2017.11.015.Search in Google Scholar PubMed

Elfawy, H.A. and Das, B. (2019). Crosstalk between mitochondrial dysfunction, oxidative stress, and age related neurodegenerative disease: etiologies and therapeutic strategies. Life Sci. 218: 165–184, https://doi.org/10.1016/j.lfs.2018.12.029.Search in Google Scholar PubMed

Esmaeili, Y., Yarjanli, Z., Pakniya, F., Bidram, E., Łos, M.J., Eshraghi, M., Klionsky, D.J., Ghavami, S., and Zarrabi, A. (2022). Targeting autophagy, oxidative stress, and ER stress for neurodegenerative disease treatment. J. Control Release 345: 147–175, https://doi.org/10.1016/j.jconrel.2022.03.001.Search in Google Scholar PubMed

Fallon, J.H. and Seroogy, K.B. (1985). The distribution and some connections of cholecystokinin neurons in the rat brain. Ann. N. Y. Acad. Sci. 448: 121–132, https://doi.org/10.1111/j.1749-6632.1985.tb29912.x.Search in Google Scholar PubMed

Fasano, A., Visanji, N.P., Liu, L.W., Lang, A.E., and Pfeiffer, R.F. (2015). Gastrointestinal dysfunction in Parkinson’s disease. Lancet Neurol. 14: 625–639, https://doi.org/10.1016/s1474-4422(15)00007-1.Search in Google Scholar

Feng, H., Su, J., Fang, W., Chen, X., and He, J. (2021). The entorhinal cortex modulates trace fear memory formation and neuroplasticity in the mouse lateral amygdala via cholecystokinin. eLife 10, https://doi.org/10.7554/elife.69333.Search in Google Scholar PubMed PubMed Central

Ferrucci, M., Pasquali, L., Paparelli, A., Ruggieri, S., and Fornai, F. (2008). Pathways of methamphetamine toxicity. Ann. N. Y. Acad. Sci. 1139: 177–185, https://doi.org/10.1196/annals.1432.013.Search in Google Scholar PubMed

Gerhardt, P., Voits, M., Fink, H., and Huston, J.P. (1994). Evidence for mnemotropic action of cholecystokinin fragments Boc-CCK-4 and CCK-8S. Peptides 15: 689–697, https://doi.org/10.1016/0196-9781(94)90097-3.Search in Google Scholar PubMed

Gibbs, J., Young, R.C., and Smith, G.P. (1973). Cholecystokinin decreases food intake in rats. J. Comp. Physiol. Psychol. 84: 488–495, https://doi.org/10.1037/h0034870.Search in Google Scholar PubMed

Gou, H., Sun, D., Hao, L., An, M., Xie, B., Cong, B., Ma, C., and Wen, D. (2020). Cholecystokinin-8 attenuates methamphetamine-induced inflammatory activation of microglial cells through CCK2 receptor. Neurotox 81: 70–79, https://doi.org/10.1016/j.neuro.2020.09.001.Search in Google Scholar PubMed

Gronier, B. and Debonnel, G. (1995). CCKB receptors mediate CCK-8S-induced activation of dorsal hippocampus CA3 pyramidal neurons: an in vivo electrophysiological study in the rat. Synapse 21: 158–168, https://doi.org/10.1002/syn.890210209.Search in Google Scholar PubMed

Hao, L., Shi, M., Ma, J., Shao, S., Yuan, Y., Liu, J., Yu, Z., Zhang, Z., Hölscher, C., and Zhang, Z. (2024). A cholecystokinin analogue ameliorates cognitive deficits and regulates mitochondrial dynamics via the AMPK/Drp1 pathway in APP/PS1 mice. J. Prev. Alzheimers. Dis. 11: 382–401, https://doi.org/10.14283/jpad.2024.6.Search in Google Scholar PubMed

Harman, D. (1956). Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11: 298–300, https://doi.org/10.1093/geronj/11.3.298.Search in Google Scholar PubMed

Hassan, A., Sharma Kandel, R., Mishra, R., Gautam, J., Alaref, A., and Jahan, N. (2020). Diabetes mellitus and Parkinson’s disease: shared pathophysiological links and possible therapeutic implications. Cureus 12: e9853, https://doi.org/10.7759/cureus.9853.Search in Google Scholar PubMed PubMed Central

Hoffmann, P., Eberlein, G.A., Reeve, J.R.Jr., Bünte, R.H., Grandt, D., Goebell, H., and Eysselein, V.E. (1993). Comparison of clearance and metabolism of infused cholecystokinins 8 and 58 in dogs. Gastroenterology 105: 1732–1736, https://doi.org/10.1016/0016-5085(93)91070-x.Search in Google Scholar PubMed

Hölscher, C. (2019). Insulin signaling impairment in the brain as a Risk factor in Alzheimer’s disease. Front Aging Neurosci. 11: 88, https://doi.org/10.3389/fnagi.2019.00088.Search in Google Scholar PubMed PubMed Central

Hölscher, C. (2022). Glucagon-like peptide 1 and glucose-dependent insulinotropic peptide hormones and novel receptor agonists protect synapses in Alzheimer’s and Parkinson’s diseases. Front Synaptic Neurosci. 14: 955258, https://doi.org/10.3389/fnsyn.2022.955258.Search in Google Scholar PubMed PubMed Central

Huston, J.P., Schildein, S., Gerhardt, P., Privou, C., Fink, H., and Hasenöhrl, R.U. (1998). Modulation of memory, reinforcement and anxiety parameters by intra-amygdala injection of cholecystokinin-fragments Boc-CCK-4 and CCK-8s. Peptides 19: 27–37, https://doi.org/10.1016/s0196-9781(97)00270-2.Search in Google Scholar PubMed

Jorfi, M., Maaser-Hecker, A., and Tanzi, R.E. (2023). The neuroimmune axis of Alzheimer’s disease. Genome. Med. 15: 6, https://doi.org/10.1186/s13073-023-01155-w.Search in Google Scholar PubMed PubMed Central

Karson, M.A., Whittington, K.C., and Alger, B.E. (2008). Cholecystokinin inhibits endocannabinoid-sensitive hippocampal IPSPs and stimulates others. Neuropharmacol. 54: 117–128, https://doi.org/10.1016/j.neuropharm.2007.06.023.Search in Google Scholar PubMed PubMed Central

Keil, U., Bonert, A., Marques, C.A., Scherping, I., Weyermann, J., Strosznajder, J.B., Müller-Spahn, F., Haass, C., Czech, C., Pradier, L., et al.. (2004). Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis. J. Biol. Chem. 279: 50310–50320, https://doi.org/10.1074/jbc.m405600200.Search in Google Scholar PubMed

Khaidakov, M., Heflich, R.H., Manjanatha, M.G., Myers, M.B., and Aidoo, A. (2003). Accumulation of point mutations in mitochondrial DNA of aging mice. Mutation Res. 526: 1–7, https://doi.org/10.1016/s0027-5107(03)00010-1.Search in Google Scholar PubMed

Kim, S., Kwon, S.H., Kam, T.I., Panicker, N., Karuppagounder, S.S., Lee, S., Lee, J.H., Kim, W.R., Kook, M., Foss, C.A., et al.. (2019). Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson’s disease. Neuron 103: 627–641.e627, https://doi.org/10.1016/j.neuron.2019.05.035.Search in Google Scholar PubMed PubMed Central

Kim, Y.Y., Um, J.H., Yoon, J.H., Lee, D.Y., Lee, Y.J., Kim, D.H., Park, J.I., and Yun, J. (2020). p53 regulates mitochondrial dynamics by inhibiting Drp1 translocation into mitochondria during cellular senescence. FASEB journal 34: 2451–2464, https://doi.org/10.1096/fj.201901747rr.Search in Google Scholar PubMed

Klemmensen, M.M., Borrowman, S.H., Pearce, C., Pyles, B., and Chandra, B. (2024). Mitochondrial dysfunction in neurodegenerative disorders. Neurother 21: e00292, https://doi.org/10.1016/j.neurot.2023.10.002.Search in Google Scholar PubMed PubMed Central

Knudsen, L.B. and Lau, J. (2019). The discovery and development of liraglutide and semaglutide. Front Endocrinol. 10: 155, https://doi.org/10.3389/fendo.2019.00155.Search in Google Scholar PubMed PubMed Central

Lau, S.H., Young, C.H., Zheng, Y., and Chen, X. (2023). The potential role of the cholecystokinin system in declarative memory. Neurochem. Int. 162: 105440, https://doi.org/10.1016/j.neuint.2022.105440.Search in Google Scholar PubMed

Lester-Coll, N., Rivera, E.J., Soscia, S.J., Doiron, K., Wands, J.R., and de la Monte, S.M. (2006). Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer’s disease. J. Alz. Dis. 9: 13–33, https://doi.org/10.3233/jad-2006-9102.Search in Google Scholar PubMed

Li, C., Liu, W., Li, X., Zhang, Z., Qi, H., Liu, S., Yan, N., Xing, Y., Hölscher, C., and Wang, Z. (2020). The novel GLP-1/GIP analogue DA5-CH reduces tau phosphorylation and normalizes theta rhythm in the icv. STZ rat model of AD. Brain behav. 10: e01505, https://doi.org/10.1002/brb3.1505.Search in Google Scholar PubMed PubMed Central

Li, J., Wang, Y., Wang, Y., Wen, X., Ma, X.N., Chen, W., Huang, F., Kou, J., Qi, L.W., Liu, B., et al.. (2015). Pharmacological activation of AMPK prevents Drp1-mediated mitochondrial fission and alleviates endoplasmic reticulum stress-associated endothelial dysfunction. J. Mol. Cell. Cardiol. 86: 62–74, https://doi.org/10.1016/j.yjmcc.2015.07.010.Search in Google Scholar PubMed

Li, Y., Bader, M., Tamargo, I., Rubovitch, V., Tweedie, D., Pick, C.G., and Greig, N.H. (2015). Liraglutide is neurotrophic and neuroprotective in neuronal cultures and mitigates mild traumatic brain injury in mice. J. Neurochem. 135: 1203–1217, https://doi.org/10.1111/jnc.13169.Search in Google Scholar PubMed PubMed Central

Li, Y., Perry, T., Kindy, M.S., Harvey, B.K., Tweedie, D., Holloway, H.W., Powers, K., Shen, H., Egan, J.M., Sambamurti, K., et al.. (2009). GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc. Natl. Acad. Sci. U. S. A. 106: 1285–1290, https://doi.org/10.1073/pnas.0806720106.Search in Google Scholar PubMed PubMed Central

Liu, Y.J., Liu, T.T., Jiang, L.H., Liu, Q., Ma, Z.L., Xia, T.J., and Gu, X.P. (2021). Identification of hub genes associated with cognition in the hippocampus of Alzheimer’s Disease. Bioengineered 12: 9598–9609, https://doi.org/10.1080/21655979.2021.1999549.Search in Google Scholar PubMed PubMed Central

Lo, C.M., Samuelson, L.C., Chambers, J.B., King, A., Heiman, J., Jandacek, R.J., Sakai, R.R., Benoit, S.C., Raybould, H.E., Woods, S.C., et al.. (2008). Characterization of mice lacking the gene for cholecystokinin. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294: R803–R810, https://doi.org/10.1152/ajpregu.00682.2007.Search in Google Scholar PubMed

Magni, P., Ruscica, M., Dozio, E., Rizzi, E., Beretta, G., and Maffei Facino, R. (2012). Parthenolide inhibits the LPS-induced secretion of IL-6 and TNF-α and NF-κB nuclear translocation in BV-2 microglia. Phytother. Res. 26: 1405–1409, https://doi.org/10.1002/ptr.3732.Search in Google Scholar PubMed

Manni, L. and Lundeberg, T. (2003). Effects of cholecystokinin-8 in peripheral neuropathies: a nerve growth factor mediated action? Arch. Ital. Biol. 141: 117–126.Search in Google Scholar

Mantzavinos, V. and Alexiou, A. (2017). Biomarkers for Alzheimer’s disease diagnosis. Current Alz. Res. 14: 1149–1154, https://doi.org/10.2174/1567205014666170203125942.Search in Google Scholar PubMed PubMed Central

Maskery, M., Goulding, E.M., Gengler, S., Melchiorsen, J.U., Rosenkilde, M.M., and Holscher, C. (2020). The dual GLP-1/GIP receptor agonist DA4-JC shows superior protective properties compared to the GLP-1 analogue liraglutide in the APP/PS1 mouse model of Alzheimer’s disease. Am. J. Alzheimers Dis. Other Demen. 35: 1533317520953041, https://doi.org/10.1177/1533317520953041.Search in Google Scholar PubMed PubMed Central

Mattson, M.P., Gleichmann, M., and Cheng, A. (2008). Mitochondria in neuroplasticity and neurological disorders. Neuron 60: 748–766, https://doi.org/10.1016/j.neuron.2008.10.010.Search in Google Scholar PubMed PubMed Central

May, A.A., Liu, M., Woods, S.C., and Begg, D.P. (2016). CCK increases the transport of insulin into the brain. Physiol. Behav. 165: 392–397, https://doi.org/10.1016/j.physbeh.2016.08.025.Search in Google Scholar PubMed PubMed Central

McRoberts, J.W. (1986). Cholecystokinin and pain: a review. Anesth. Prog. 33: 87–90.Search in Google Scholar

Meissner, W., Remy, P., Giordana, C., Maltete, D., Derkinderen, P., Houeto, J., Arnheim, M., Benatru, I., Boraud, T., Brefel-Courbon, N., et al.. (2024). Trial of lixisenatide in early Parkinson’s disease. New Eng. J. Med. 390: 1176–1185, https://doi.org/10.1056/nejmoa2312323.Search in Google Scholar

Monzio Compagnoni, G., Di Fonzo, A., Corti, S., Comi, G.P., Bresolin, N., and Masliah, E. (2020). The role of mitochondria in neurodegenerative diseases: the lesson from Alzheimer’s disease and Parkinson’s disease. Molec. Neurobiol. 57: 2959–2980, https://doi.org/10.1007/s12035-020-01926-1.Search in Google Scholar PubMed PubMed Central

Moran, T.H., Robinson, P.H., Goldrich, M.S., and McHugh, P.R. (1986). Two brain cholecystokinin receptors: implications for behavioral actions. Brain Res. 362: 175–179, https://doi.org/10.1016/0006-8993(86)91413-7.Search in Google Scholar PubMed

Mou, Y., Du, Y., Zhou, L., Yue, J., Hu, X., Liu, Y., Chen, S., Lin, X., Zhang, G., Xiao, H., et al.. (2022). Gut microbiota interact with the brain through systemic chronic inflammation: implications on neuroinflammation, neurodegeneration, and aging. Front Immunol. 13: 796288, https://doi.org/10.3389/fimmu.2022.796288.Search in Google Scholar PubMed PubMed Central

Müller, T.D., Finan, B., Bloom, S.R., D’Alessio, D., Drucker, D.J., Flatt, P.R., Fritsche, A., Gribble, F., Grill, H.J., Habener, J.F., et al.. (2019). Glucagon-like peptide 1 (GLP-1). Mol. Metab. 30: 72–130, https://doi.org/10.1016/j.molmet.2019.09.010.Search in Google Scholar PubMed PubMed Central

Neidigh, J.W., Fesinmeyer, R.M., Prickett, K.S., and Andersen, N.H. (2001). Exendin-4 and glucagon-like-peptide-1: NMR structural comparisons in the solution and micelle-associated states. Biochem 40: 13188–13200, https://doi.org/10.1021/bi010902s.Search in Google Scholar PubMed

Nikolaus, S., Huston, J.P., and Schwarting, R.K. (1999). Pretreatment with fragments of substance-P or with cholecystokinin differentially affects recovery from sub-total nigrostriatal 6-hydroxydopamine lesion. Neural Plast. 6: 77–89, https://doi.org/10.1155/np.1999.77.Search in Google Scholar

Nilsson, A., Fälth, M., Zhang, X., Kultima, K., Sköld, K., Svenningsson, P., and Andrén, P.E. (2009). Striatal alterations of secretogranin-1, somatostatin, prodynorphin, and cholecystokinin peptides in an experimental mouse model of Parkinson disease. Molec. Cell Proteomics 8: 1094–1104, https://doi.org/10.1074/mcp.m800454-mcp200.Search in Google Scholar PubMed PubMed Central

Pandey, S., Mangmool, S., Madreiter-Sokolowski, C.T., Wichaiyo, S., Luangmonkong, T., and Parichatikanond, W. (2023). Exendin-4 protects against high glucose-induced mitochondrial dysfunction and oxidative stress in SH-SY5Y neuroblastoma cells through GLP-1 receptor/Epac/Akt signaling. Euro. J. Pharmacol. 954: 175896, https://doi.org/10.1016/j.ejphar.2023.175896.Search in Google Scholar PubMed

Paoli, A., Bosco, G., Camporesi, E.M., and Mangar, D. (2015). Ketosis, ketogenic diet and food intake control: a complex relationship. Front Psychol. 6: 27, https://doi.org/10.3389/fpsyg.2015.00027.Search in Google Scholar PubMed PubMed Central

Plagman, A., Hoscheidt, S., McLimans, K.E., Klinedinst, B., Pappas, C., Anantharam, V., Kanthasamy, A., and Willette, A.A. (2019). Cholecystokinin and Alzheimer’s disease: a biomarker of metabolic function, neural integrity, and cognitive performance. Neurobiol. Aging 76: 201–207, https://doi.org/10.1016/j.neurobiolaging.2019.01.002.Search in Google Scholar PubMed PubMed Central

Poewe, W., Seppi, K., Tanner, C.M., Halliday, G.M., Brundin, P., Volkmann, J., Schrag, A.E., and Lang, A.E. (2017). Parkinson disease. Nat. Rev. Dis. Primers 3: 17013, https://doi.org/10.1038/nrdp.2017.13.Search in Google Scholar PubMed

Preston, C.C., Oberlin, A.S., Holmuhamedov, E.L., Gupta, A., Sagar, S., Syed, R.H., Siddiqui, S.A., Raghavakaimal, S., Terzic, A., and Jahangir, A. (2008). Aging-induced alterations in gene transcripts and functional activity of mitochondrial oxidative phosphorylation complexes in the heart. Mechan. Ageing Dev. 129: 304–312, https://doi.org/10.1016/j.mad.2008.02.010.Search in Google Scholar PubMed PubMed Central

Price, D.D., von der Gruen, A., Miller, J., Rafii, A., and Price, C. (1985). Potentiation of systemic morphine analgesia in humans by proglumide, a cholecystokinin antagonist. Anesth. Analg. 64: 801–806.10.1213/00000539-198508000-00010Search in Google Scholar

Rangel Guerrero, D.K., Balueva, K., Barayeu, U., Baracskay, P., Gridchyn, I., Nardin, M., Roth, C.N., Wulff, P., and Csicsvari, J. (2024). Hippocampal cholecystokinin-expressing interneurons regulate temporal coding and contextual learning. Neuron 112: 2045–2061.e10, https://doi.org/10.1016/j.neuron.2024.03.019.Search in Google Scholar PubMed

Rango, M. and Bresolin, N. (2018). Brain mitochondria, aging, and Parkinson’s disease. Genes 9, https://doi.org/10.3390/genes9050250.Search in Google Scholar PubMed PubMed Central

Rehfeld, J.F. (2017). Cholecystokinin-from local gut hormone to ubiquitous messenger. Front Endocrinol. 8: 47, https://doi.org/10.3389/fendo.2017.00047.Search in Google Scholar PubMed PubMed Central

Reich, N. and Holscher, C. (2024). Cholecystokinin (CCK): a neuromodulator with therapeutic potential in Alzheimer’s and Parkinson’s disease. Front Neuroendocrinol. 73: 101122, https://doi.org/10.1016/j.yfrne.2024.101122.Search in Google Scholar PubMed

Reich, N. and Hölscher, C. (2022). The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: an in-depth review. Front Neurosci. 16: 970925, https://doi.org/10.3389/fnins.2022.970925.Search in Google Scholar PubMed PubMed Central

Saia, R.S., Mestriner, F.L., Bertozi, G., Cunha, F.Q., and Cárnio, E.C. (2014). Cholecystokinin inhibits inducible nitric oxide synthase expression by lipopolysaccharide-stimulated peritoneal macrophages. Mediators Inflamm. 2014: 896029, https://doi.org/10.1155/2014/896029.Search in Google Scholar PubMed PubMed Central

Schapira, A.H., Cooper, J.M., Dexter, D., Jenner, P., Clark, J.B., and Marsden, C.D. (1989). Mitochondrial complex I deficiency in Parkinson’s disease. Lancet 1: 1269, https://doi.org/10.1016/s0140-6736(89)92366-0.Search in Google Scholar PubMed

Seroogy, K.B., Dangaran, K., Lim, S., Haycock, J.W., and Fallon, J.H. (1989). Ventral mesencephalic neurons containing both cholecystokinin- and tyrosine hydroxylase-like immunoreactivities project to forebrain regions. J. Comp. Neurol. 279: 397–414, https://doi.org/10.1002/cne.902790306.Search in Google Scholar PubMed

Shinohara, S. and Kawasaki, K. (1997). Electrophysiological changes in rat hippocampal pyramidal neurons produced by cholecystokinin octapeptide. Neuroscience 78: 1005–1016, https://doi.org/10.1016/s0306-4522(96)00653-7.Search in Google Scholar PubMed

Simpson, D.S.A. and Oliver, P.L. (2020). ROS generation in microglia: understanding oxidative stress and inflammation in neurodegenerative disease. Antioxidants 9, https://doi.org/10.3390/antiox9080743.Search in Google Scholar PubMed PubMed Central

Su, L., Feng, L., Song, Q., Kang, H., Zhang, X., Liang, Z., Jia, Y., Feng, D., Liu, C., and Xie, L. (2013). Diagnostic value of dynamics serum sCD163, sTREM-1, PCT, and CRP in differentiating sepsis, severity assessment, and prognostic prediction. Mediators Inflamm. 2013: 969875, https://doi.org/10.1155/2013/969875.Search in Google Scholar PubMed PubMed Central

Su, Y., Liu, N., Zhang, Z., Li, H., Ma, J., Yuan, Y., Shi, M., Liu, J., Zhang, Z., Holscher, C., et al.. (2022). Cholecystokinin and glucagon-like peptide-1 analogues regulate intestinal tight junction, inflammation, dopaminergic neurons and α-synuclein accumulation in the colon of two Parkinson’s disease mouse models. Euro. J. Pharmacol. 926: 175029, https://doi.org/10.1016/j.ejphar.2022.175029.Search in Google Scholar PubMed

Sun, N., Yun, J., Liu, J., Malide, D., Liu, C., Rovira, I.I., Holmström, K.M., Fergusson, M.M., Yoo, Y.H., Combs, C.A., et al.. (2015). Measuring in vivo mitophagy. Molec. cell 60: 685–696, https://doi.org/10.1016/j.molcel.2015.10.009.Search in Google Scholar PubMed PubMed Central

Tirassa, P. and Costa, N. (2007). CCK-8 induces NGF and BDNF synthesis and modulates TrkA and TrkB expression in the rat hippocampus and septum: effects on kindling development. Neurochem. Int. 50: 130–138, https://doi.org/10.1016/j.neuint.2006.07.008.Search in Google Scholar PubMed

Verbaeys, I., León-Tamariz, F., Buyse, J., Decuypere, E., Pottel, H., and Cokelaere, M. (2009). Lack of tolerance development with long-term administration of PEGylated cholecystokinin. Peptides 30: 699–704, https://doi.org/10.1016/j.peptides.2008.11.010.Search in Google Scholar PubMed

Voits, M., Hasenohrl, R.U., Huston, J.P., and Fink, H. (2001). Repeated treatment with cholecystokinin octapeptide improves maze performance in aged Fischer 344 rats. Peptides 22: 1325–1330, https://doi.org/10.1016/s0196-9781(01)00459-4.Search in Google Scholar PubMed

Wang, M., Zhang, H., Liang, J., Huang, J., and Chen, N. (2023). Exercise suppresses neuroinflammation for alleviating Alzheimer’s disease. J. Neuroinflamm. 20: 76, https://doi.org/10.1186/s12974-023-02753-6.Search in Google Scholar PubMed PubMed Central

Warrilow, A., Turner, M., Naumovski, N., and Somerset, S. (2022). Role of cholecystokinin in satiation: a systematic review and meta-analysis. Br. J. Nutr.: 1–9, https://doi.org/10.1017/s0007114522000381.Search in Google Scholar

Wegmann, S., Biernat, J., and Mandelkow, E. (2021). A current view on Tau protein phosphorylation in Alzheimer’s disease. Curr. Opin. Neurobiol. 69: 131–138, https://doi.org/10.1016/j.conb.2021.03.003.Search in Google Scholar PubMed

Wen, D., An, M., Gou, H., Liu, X., Liu, L., Ma, C., and Cong, B. (2016). Cholecystokinin-8 inhibits methamphetamine-induced neurotoxicity via an anti-oxidative stress pathway. Neurotox 57: 31–38, https://doi.org/10.1016/j.neuro.2016.08.008.Search in Google Scholar PubMed

Xu, L., He, D., and Bai, Y. (2016). Microglia-mediated inflammation and neurodegenerative disease. Molec. Neurobiol. 53: 6709–6715, https://doi.org/10.1007/s12035-015-9593-4.Search in Google Scholar PubMed

You, Z.B., Herrera-Marschitz, M., Pettersson, E., Nylander, I., Goiny, M., Shou, H.Z., Kehr, J., Godukhin, O., Hökfelt, T., Terenius, L., et al.. (1996). Modulation of neurotransmitter release by cholecystokinin in the neostriatum and substantia nigra of the rat: regional and receptor specificity. Neuroscience 74: 793–804, https://doi.org/10.1016/0306-4522(96)00149-2.Search in Google Scholar PubMed

Zetler, G. (1980). Analgesia and ptosis caused by caerulein and cholecystokinin octapeptide (CCK-8). Neuropharmacology 19: 415–422, https://doi.org/10.1016/0028-3908(80)90047-7.Search in Google Scholar PubMed

Zhang, K., Liao, P., Wen, J., and Hu, Z. (2023a). Synaptic plasticity in schizophrenia pathophysiology. IBRO Neurosci. Rep. 14: 244–252, https://doi.org/10.1016/j.ibneur.2023.01.008.Search in Google Scholar PubMed PubMed Central

Zhang, L., Li, C., Zhang, Z., Zhang, Z., Jin, Q.Q., Li, L., and Hölscher, C. (2022). DA5-CH and Semaglutide protect against neurodegeneration and reduce α-synuclein levels in the 6-OHDA Parkinson’s disease rat model. Parkinsons Dis. 2022: 1428817, https://doi.org/10.1155/2022/1428817.Search in Google Scholar PubMed PubMed Central

Zhang, L., Trushin, S., Christensen, T.A., Bachmeier, B.V., Gateno, B., Schroeder, A., Yao, J., Itoh, K., Sesaki, H., Poon, W.W., et al.. (2016). Altered brain energetics induces mitochondrial fission arrest in Alzheimer’s Disease. Sci. Rep. 6: 18725, https://doi.org/10.1038/srep18725.Search in Google Scholar PubMed PubMed Central

Zhang, L.L., Wei, X.F., Zhang, Y.H., Xu, S.J., Chen, X.W., Wang, C., and Wang, Q.W. (2013). CCK-8S increased the filopodia and spines density in cultured hippocampal neurons of APP/PS1 and wild-type mice. Neurosci. Lett. 542: 47–52, https://doi.org/10.1016/j.neulet.2013.03.023.Search in Google Scholar PubMed

Zhang, X., Asim, M., Fang, W., Md Monir, H., Wang, H., Kim, K., Feng, H., Wang, S., Sesaki, H., Poon, W.W., et al.. (2023c). Cholecystokinin B receptor antagonists for the treatment of depression via blocking long-term potentiation in the basolateral amygdala. Molec. Psychiat. 28: 3459–3474, https://doi.org/10.1038/s41380-023-02127-7.Search in Google Scholar PubMed

Zhang, X., Grosfeld, A., Williams, E., Vasiliauskas, D., Barretto, S., Smith, L., Mariadassou, M., Philippe, C., Devime, F., Melchior, C., et al.. (2019). Fructose malabsorption induces cholecystokinin expression in the ileum and cecum by changing microbiota composition and metabolism. FASEB journal 33: 7126–7142, https://doi.org/10.1096/fj.201801526rr.Search in Google Scholar PubMed PubMed Central

Zhang, Z., Li, H., Su, Y., Ma, J., Yuan, Y., Yu, Z., Shi, M., Shao, S., Zhang, Z., and Hölscher, C. (2022). Neuroprotective effects of a cholecystokinin analogue in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Parkinson’s disease mouse model. Front Neurosci. 16: 814430, https://doi.org/10.3389/fnins.2022.814430.Search in Google Scholar PubMed PubMed Central

Zhang, Z., Yu, Z., Yuan, Y., Yang, J., Wang, S., Ma, H., Hao, L., Ma, J., Zhang, Z., Hölscher, C., et al.. (2023b). Cholecystokinin signaling can rescue cognition and synaptic plasticity in the APP/PS1 mouse model of Alzheimer’s disease. Molec. Neurobiol. 60: 5067–5089, https://doi.org/10.1007/s12035-023-03388-7.Search in Google Scholar PubMed

Zhang, Z.Q. and Hölscher, C. (2020). GIP has neuroprotective effects in Alzheimer and Parkinson’s disease models. Peptides 125: 170184, https://doi.org/10.1016/j.peptides.2019.170184.Search in Google Scholar PubMed

Received: 2024-10-07

Accepted: 2024-12-13

Published Online: 2025-01-21

Published in Print: 2025-06-26

Articles in the same Issue

https://doi.org/10.1515/revneuro-2024-0142

Keywords for this article

cholecystokinin; neuroprotection; chronic inflammation; synaptic plasticity; oxidative stress