Antidepressant and anxiolytic-like, sedation and hypnosis

Under the article category “Behavior and Neuroprotection”, four articles are presented in this issue of the Journal of Basic and Clinical Physiology and Pharmacology exploring compounds affecting behavior in rat and mouse experimental models. These studies tell us how hypothesis-driven research can evolve into products that interact with the serotonergic network and how can herbal products assist development of readily available neuroprotective agents.

The first two articles by Bhatt et al. [1] “Neuropharmacological and neurochemical evaluation of N-n-propyl-3-ethoxyquinoxaline-2-carboxamide (6n): a novel serotonergic 5-HT3 receptor antagonist for co-morbid antidepressant- and anxiolytic-like potential using traumatic brain injury model in rats” and [2] “Neuropharmacological evaluation of a novel 5-HT3 receptor antagonist (4-benzylpiperazin-1-yl) (3-methoxyquinoxalin-2-yl) methanone (6g) on lipopolysaccharide-induced anxiety models in mice” evaluate the properties of a novel drug 6n, a serotonergic 5-HT3 receptor antagonist, as a potential antidepressant and anxiolytic drug. Serotonin is the major neurotransmitter involved in depression, and this compound was designed based on the hypothesis of Rajkumar and Mahesh [3] that postsynaptic 5-HT3 receptor antagonists can facilitate specific binding of 5-HT to other postsynaptic receptors such as 5-HT1B, 5-HT2A, and 5-HT2C, thereby aiding serotonergic transmission. Studies on 5-HT3A knockout mice further confirmed the role of 5-HT3 receptor subtypes in depression and anxiety-related behaviors [4]. Bhatt et al. use a battery of behavioral tests to show the efficiency of 6n during exposure to two stressors. In Lipopolysaccharide-induced anxiety symptoms in mice, three behavioral paradigms were applied to measure the impact of chronic treatment with 6n on anxiety attenuation and serotonin level. The compound affected serotonin signaling, possibly by enhancing serotonergic transmission. The second model used by Bhatt’s team was a traumatic brain injury rat model. Behavioral experimental paradigms as well as assays measuring serotonin, norepinephrine and brain-derived neurotrophic factor levels confirmed the efficiency of 6n. This compound has an optimum log P (2.52) and pA2 values (7.6) greater than the standard 5-HT3 receptor antagonist, ondansetron (pA2–6.9).

The third paper in this category is by Rajashree et al. “Effect of Salacia reticulata W. and Clitoria ternatea L. on the cognitive and behavioral enhancement in the streptozotocin-induced young diabetic rats” [5]. The structural and functional interaction of neurons with the surrounding vasculature is critical for proper function of the central nervous system, including learning and memory [6]. Thus, diabetic patients may suffer cognitive impairments which affect quality of life. Using a plus maze, and a Morris water maze, Rajashree et al. attempted to elucidate whether the combination of two herbal formulas has a beneficial effect on central cognitive pathologies caused by stretozotocin-induced diabetes in young rats. The combined nootropic treatment was found to be beneficial in young rats during-onset diabetes, being preventive but not curative. The authors hypothesize that the memory enhancement might also be beneficial to those with deficiencies not related to diabetes. The study is descriptive, and calls for future mechanistic studies.

The last article published under the category “Behavior and Neuroprotection” is by Md. Jakaria et al. and entitled “In vivo sedative and hypnotic activities of methanol extract from the leaves of Jacquemontia paniculata (Burm.f.) Hallier f. in Swiss Albino mice” [7]. Jacquemontia is one of the superior genera belonging to Convolvulaceae, and includes approximately 120 species [8]. Jacquemontia pentantha leaves contain several flavonoid species, with anti-oxidative, anti-hyperglycemic, and anti-inflammatory activities. Psychotomimetic ergot alkaloids have been also detected. It has neuro-pharmacological impacts, as well as hypnotic and sedative activity and the current study attempts to provide the scientific basis of its use in traditional medicine. The authors employ pharmacological behavioral tests and compare the crude leaf extract (containing a mixture of carbohydrates, flavonoids, phenols, tannins, saponins, phytosterols, fixed oils, and glycosides) to conventional anxiolytic medications such as diazepam and thiopental sodium-induced sleeping time determination test, which is used to test sedation and hypnosis. The results of this investigation prove that the J. pentantha leaf extract has sedative and hypnotic activities. Future research may enable development of herbal allopathic drugs to treat sleep disorders.