Home Developmental effects of early-life stress on dopamine D2 receptor and proteins involved in noncanonical D2 dopamine receptor signaling pathway in the prefrontal cortex of male rats
Article
Licensed
Unlicensed Requires Authentication

Developmental effects of early-life stress on dopamine D2 receptor and proteins involved in noncanonical D2 dopamine receptor signaling pathway in the prefrontal cortex of male rats

  • Maryam Mahmoodkhani , Maedeh Ghasemi , Leila Derafshpour , Mohammad Amini and Nasrin Mehranfard EMAIL logo
Published/Copyright: May 7, 2021
Journal of Complementary and Integrative Medicine
From the journal Journal of Complementary and Integrative Medicine Volume 19 Issue 3

Abstract

Objectives

Dopamine neurotransmission is implicated in multiple neuropsychiatric disorders, most strikingly in Parkinson’s disease, bipolar disorder, attention-deficit hyperactivity disorder and schizophrenia. In addition to canonical pathway, D2-receptor (D2R) exerts some of its biological actions through regulating the activity of Akt and GSK3, which in turn were found to be altered in several psychiatric illnesses. The present study examined the impacts of maternal separation, an early-life stress model which has been associated with disturbed neurodevelopment and appearance of many psychiatric disorders, on developmental changes in dopamine concentration and the expression of D2Rs, Akt and GSK-3β in the medial prefrontal cortex (PFC; a key target of stress) in adolescent and young adult male rats.

Methods

Maternal separation was performed 3 h per day from postnatal days 2 to 11. The PFC protein and dopamine contents were determined using western blotting analysis and Eliza, respectively.

Results

Results indicated long-term increases in the prefrontal dopamine levels in stressed adolescent and young adult male rats, accompanied by significant downregulation of D2R as well as upregulation of p-Akt and GSK-3β contents in stressed adolescence compared to controls, with all protein levels that returned to control values in stressed adult rats.

Conclusions

Our findings suggest that early-life stress differentially modulates prefrontal D2R/Akt/GSK-3β levels during development. Since adolescence period is susceptible to the onset of specific mental illnesses, disruption of noncanonical components of D2R signaling during this critical period may have an important role in programming neurobehavioral phenotypes in adulthood and manipulations influencing Akt/GSK-3β pathway may improve the expression of specific dopamine-related behaviors and the effects of dopaminergic drugs.

Keywords: adolescence; dopamine; D2-receptor; early-life stress; GSK-3β; prefrontal cortex; rat
Corresponding author: Nasrin Mehranfard, Neurophysiology Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran, E-mail:
Maedeh Ghasemi and Leila Derafshpour have contributed equally to this work.

Funding source: Urmia University of Medical Sciences

Acknowledgments

The authors acknowledge the support provided by the Neurophysiology Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences.

  1. Research funding: This work was supported by Neurophysiology Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences.

  2. Author contributions: Nasrin Mehranfard conceived and designed the experiments. Maryam Mahmoodkhani, Leila Derafshpour and Mohammad Amini performed the experiments. Nasrin Mehranfard and Maedeh Ghasemi analyzed and interpreted the data. Nasrin Mehranfard wrote the manuscript and Maedeh Ghasemi participated in all revisions of manuscript drafts.

  3. Conflict of interest: The authors have declared no conflict of interest.

  4. Ethics approval: All experiments were conducted in agreement with the National Institutes of animal care and use guidelines approved by the Institutional Ethic Committee (IEC) at Urmia University of Medical Sciences (IR.UMSU.REC.1397.253).

References

1. Heim, C, Plotsky, PM, Nemeroff, CB. Importance of studying the contributions of early adverse experience to neurobiological findings in depression. Neuropsychopharmacology 2004;29:641–8. https://doi.org/10.1038/sj.npp.1300397.Search in Google Scholar

2. Oswald, LM, Wand, GS, Kuwabara, H, Wong, DF, Zhu, S, Brasic, JR. History of childhood adversity is positively associated with ventral striatal dopamine responses to amphetamine. Psychopharmacology (Berl) 2014;231:2417–33. https://doi.org/10.1007/s00213-013-3407-z.Search in Google Scholar

3. Beaulieu, JM, Gainetdinov, RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 2011;63:182–217. https://doi.org/10.1124/pr.110.002642.Search in Google Scholar

4. Minton, GO, Young, AH, McQuade, R, Fairchild, G, Ingram, CD, Gartside, SE. Profound changes in dopaminergic neurotransmission in the prefrontal cortex in response to flattening of the diurnal glucocorticoid rhythm: implications for bipolar disorder. Neuropsychopharmacology 2009;34:2265–74. https://doi.org/10.1038/npp.2009.53.Search in Google Scholar

5. Sim, HR, Choi, TY, Lee, HJ, Kang, EY, Yoon, S, Han, PL, et al.. Role of dopamine D2 receptors in plasticity of stress-induced addictive behaviours. Nat Commun 2013;4:1579. https://doi.org/10.1038/ncomms2598.Search in Google Scholar

6. Picetti, R, Saiardi, A, Abdel Samad, T, Bozzi, Y, Baik, JH, Borrelli, E. Dopamine D2 receptors in signal transduction and behavior. Crit Rev Neurobiol 1997;11:121–42. https://doi.org/10.1615/critrevneurobiol.v11.i2-3.20.Search in Google Scholar

7. Druzin, MY, Kurzina, NP, Malinina, EP, Kozlov, AP. The effects of local application of D2 selective dopaminergic drugs into the medial prefrontal cortex of rats in a delayed spatial choice task. Behav Brain Res 2000;109:99–111. https://doi.org/10.1016/s0166-4328(99)00166-7.Search in Google Scholar

8. Zhang, Y, Bertolino, A, Fazio, L, Blasi, G, Rampino, A, Romano, R, et al.. Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. Proc Natl Acad Sci USA 2007;104:20552–7. https://doi.org/10.1073/pnas.0707106104.Search in Google Scholar PubMed PubMed Central

9. Teffer, K, Semendeferi, K. Human prefrontal cortex: evolution, development, and pathology. Prog Brain Res 2012;195:191–218. https://doi.org/10.1016/b978-0-444-53860-4.00009-x.Search in Google Scholar

10. Sutton, LP, Rushlow, WJ. The dopamine D2 receptor regulates Akt and GSK-3 via Dvl-3. Int J Neuropsychopharmacol 2012;15:965–79. https://doi.org/10.1017/s146114571100109x.Search in Google Scholar

11. Emamian, ES, Hall, D, Birnbaum, MJ, Karayiorgou, M, Gogos, JA. Convergent evidence for impaired AKT1-GSK3β signaling in schizophrenia. Nat Genet 2004;36:131–7. https://doi.org/10.1038/ng1296.Search in Google Scholar PubMed

12. Kozlovsky, N, Shanon-Weickert, C, Tomaskovic-Crook, E, Kleinman, JE, Belmaker, RH, Agam, G. Reduced GSK-3β mRNA levels in postmortem dorsolateral prefrontal cortex of schizophrenic patients. J Neural Transm 2004;111:1583–92. https://doi.org/10.1007/s00702-004-0166-3.Search in Google Scholar

13. Jope, RS, Yuskaitis, CJ, Beurel, E. Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. Neurochem Res 2007;32:577–95. https://doi.org/10.1007/s11064-006-9128-5.Search in Google Scholar

14. Woodgett, JR. Judging a protein by more than its name: GSK-3. Sci STKE 2001;2001:re12. https://doi.org/10.1126/stke.2001.100.re12.Search in Google Scholar

15. Li, YC, Gao, WJ. GSK-3β activity and hyperdopamine-dependent behaviors. Neurosci Biobehav Rev 2011;35:645–54. https://doi.org/10.1016/j.neubiorev.2010.08.001.Search in Google Scholar

16. Beaulieu, JM, Sotnikova, TD, Marion, S, Lefkowitz, RJ, Gainetdinov, RR, Caron, MG. An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 2005;122:261–73. https://doi.org/10.1016/j.cell.2005.05.012.Search in Google Scholar

17. Koros, E, Dorner-Ciossek, C. The role of glycogen synthase kinase-3beta in schizophrenia. Drug News Perspect 2007;20:437–45. https://doi.org/10.1358/dnp.2007.20.7.1149632.Search in Google Scholar

18. Li, YC, Xi, D, Roman, J, Huang, YQ, Gao, WJ. Activation of glycogen synthase kinase-3 beta is required for hyperdopamine and D2 receptor-mediated inhibition of synaptic NMDA receptor function in the rat prefrontal cortex. J Neurosci 2009;29:15551–63. https://doi.org/10.1523/jneurosci.3336-09.2009.Search in Google Scholar

19. Jackson, ME, Homayoun, H, Moghaddam, B. NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex. Proc Natl Acad Sci USA 2004;101:8467–72. https://doi.org/10.1073/pnas.0308455101.Search in Google Scholar

20. Newcomer, JW, Farber, NB, Jevtovic-Todorovic, V, Selke, G, Melson, AK, Hershey, T, et al.. Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 1999;20:106–18. https://doi.org/10.1016/s0893-133x(98)00067-0.Search in Google Scholar

21. Chocyk, A, Majcher-Maślanka, I, Dudys, D, Przyborowska, A, Wędzony, K. Impact of early-life stress on the medial prefrontal cortex functions – a search for the pathomechanisms of anxiety and mood disorders. Pharmacol Rep 2013;65:1462–70. https://doi.org/10.1016/s1734-1140(13)71506-8.Search in Google Scholar

22. Raineki, C, Moriceau, S, Sullivan, RM. Developing a neurobehavioral animal model of infant attachment to an abusive caregiver. Biol Psychiatr 2010;67:1137–45. https://doi.org/10.1016/j.biopsych.2009.12.019.Search in Google Scholar

23. Bolton, JL, Molet, J, Ivy, A, Baram, TZ. New insights into early-life stress and behavioral outcomes. Curr Opin Behav Sci 2017;14:133–9. https://doi.org/10.1016/j.cobeha.2016.12.012.Search in Google Scholar

24. Cenci, MA, Kalen, P, Mandel, RJ, Bjorklund, A. Regional differences in the regulation of dopamine and noradrenaline release in medial frontal cortex, nucleus accumbens and caudate-putamen: a microdialysis study in the rat. Brain Res 1992;581:217–28. https://doi.org/10.1016/0006-8993(92)90711-h.Search in Google Scholar

25. Inoue, T, Tsuchiya, K, Koyama, T. Regional changes in dopamine and serotonin activation with various intensity of physical and psychological stress in the rat brain. Pharmacol Biochem Behav 1994;49:911–20. https://doi.org/10.1016/0091-3057(94)90243-7.Search in Google Scholar

26. Marquez, C, Poirier, GL, Cordero, MI, Larsen, MH, Groner, A, Marquis, J, et al.. Peripuberty stress leads to abnormal aggression, altered amygdala and orbitofrontal reactivity and increased prefrontal MAOA gene expression. Transl Psychiatry 2013;3:e216. https://doi.org/10.1038/tp.2012.144.Search in Google Scholar PubMed PubMed Central

27. Watt, MJ, Burke, AR, Renner, KJ, Forster, GL. Adolescent male rats exposed to social defeat exhibit altered anxiety behavior and limbic monoamines as adults. Behav Neurosci 2009;123:564–76. https://doi.org/10.1037/a0015752.Search in Google Scholar PubMed PubMed Central

28. Wright, LD, Hebert, KE, Perrot-Sinal, TS. Periadolescent stress exposure exerts long-term effects on adult stress responding and expression of prefrontal dopamine receptors in male and female rats. Psychoneuroendocrinology 2008;33:130–42. https://doi.org/10.1016/j.psyneuen.2007.10.009.Search in Google Scholar PubMed

29. Nagano-Saito, A, Dagher, A, Booij, L, Gravel, P, Welfeld, K, Casey, KF, et al.. Stress-induced dopamine release in human medial prefrontal cortex—18 F-Fallypride/PET study in healthy volunteers. Synapse 2013;67:821–30. https://doi.org/10.1002/syn.21700.Search in Google Scholar PubMed

30. Ossewaarde, L, Qin, S, Van Marle, HJ, van Wingen, GA, Fernandez, G, Hermans, EJ. Stress-induced reduction in reward-related prefrontal cortex function. Neuroimage 2011;55:345–52. https://doi.org/10.1016/j.neuroimage.2010.11.068.Search in Google Scholar PubMed

31. Qin, S, Hermans, EJ, van Marle, HJ, Luo, J, Fernandez, G. Acute psychological stress reduces working memory-related activity in the dorsolateral prefrontal cortex. Biol Psychiatr 2009;66:25–32. https://doi.org/10.1016/j.biopsych.2009.03.006.Search in Google Scholar

32. Goldman-Rakic, PS. Regional and cellular fractionation of working memory. Proc Natl Acad Sci USA 1996;93:13473–80. https://doi.org/10.1073/pnas.93.24.13473.Search in Google Scholar

33. Murphy, BL, Arnsten, AF, Goldman-Rakic, PS, Roth, RH. Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys. Proc Natl Acad Sci USA 1996;93:1325–9. https://doi.org/10.1073/pnas.93.3.1325.Search in Google Scholar

34. Andersen, SL, Thompson, AT, Rutstein, M, Hostetter, JC, Teicher, MH. Dopamine receptor pruning in prefrontal cortex during the periadolescent period in rats. Synapse 2000;37:167–9. https://doi.org/10.1002/1098-2396(200008)37:2<167::aid-syn11>3.0.co;2-b.10.1002/1098-2396(200008)37:2<167::AID-SYN11>3.0.CO;2-BSearch in Google Scholar

35. Sinclair, D, Purves-Tyson, TD, Allen, KM, Weickert, CS. Impacts of stress and sex hormones on dopamine neurotransmission in the adolescent brain. Psychopharmacology (Berl) 2014;231:1581–99. https://doi.org/10.1007/s00213-013-3415-z.Search in Google Scholar

36. Bello, EP, Mateo, Y, Gelman, DM, Noaín, D, Shin, JH, Low, MJ, et al.. Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors. Nat Neurosci 2011;14:1033–8. https://doi.org/10.1038/nn.2862.Search in Google Scholar

37. Bozzi, Y, Vallone, D, Borrelli, E. Neuroprotective role of dopamine against hippocampal cell death. J Neurosci 2000;20:8643–9. https://doi.org/10.1523/jneurosci.20-22-08643.2000.Search in Google Scholar

38. Zhu, X, Li, T, Peng, S, Ma, X, Chen, X, Zhang, X. Maternal deprivation-caused behavioral abnormalities in adult rats relate to a non-methylation-regulated D2 receptor levels in the nucleus accumbens. Behav Brain Res 2010;209:281–8. https://doi.org/10.1016/j.bbr.2010.02.005.Search in Google Scholar

39. Eldar-Finkelman, H, Martinez, A. GSK-3 inhibitors: preclinical and clinical focus on CNS. Front Mol Neurosci 2011;4:32. https://doi.org/10.3389/fnmol.2011.00032.Search in Google Scholar

40. Hernandez, F, Borrell, J, Guaza, C, Avila, J, Lucas, JJ. Spatial learning deficit in transgenic mice that conditionally over-express GSK-3beta in the brain but do not form tau filaments. J Neurochem 2002;83:1529–33. https://doi.org/10.1046/j.1471-4159.2002.01269.x.Search in Google Scholar

41. Spittaels, K, Van den Haute, C, Van Dorpe, J, Terwel, D, Vandezande, K, Lasrado, R, et al.. Neonatal neuronal overexpression of glycogen synthase kinase-3 beta reduces brain size in transgenic mice. Neuroscience 2002;113:797–808. https://doi.org/10.1016/s0306-4522(02)00236-1.Search in Google Scholar

42. Jiang, H, Guo, W, Liang, X, Rao, YI. Both the establishment and the maintenance of neuronal polarity require active mechanisms: critical roles of GSK-3β and its upstream regulators. Cell 2005;120:123–35. https://doi.org/10.1016/s0092-8674(04)01258-9.Search in Google Scholar

43. Yoshimura, T, Kawano, Y, Arimura, N, Kawabata, S, Kikuchi, A, Kaibuchi, K. GSK-3β regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 2005;120:137–49. https://doi.org/10.1016/j.cell.2004.11.012.Search in Google Scholar PubMed

44. McKenzie, G, Ward, G, Stallwood, Y, Briend, E, Papadia, S, Lennard, A, et al.. Cellular Notch responsiveness is defined by phosphoinositide 3-kinase-dependent signals. BMC Cell Biol 2006;7:10. https://doi.org/10.1186/1471-2121-7-10.Search in Google Scholar PubMed PubMed Central

45. Wang, Y, Chan, SL, Miele, L, Yao, PJ, Mackes, J, Ingram, DK, et al.. Involvement of Notch signaling in hippocampal synaptic plasticity. Proc Natl Acad Sci USA 2004;101:9458–62. https://doi.org/10.1073/pnas.0308126101.Search in Google Scholar PubMed PubMed Central

46. Zhou, FQ, Snider, WD. GSK-3β and microtubule assembly in axons. Science 2005;308:211–4. https://doi.org/10.1126/science.1110301.Search in Google Scholar PubMed

47. Duda, P, Wiśniewski, J, Wójtowicz, T, Wójcicka, O, Jaśkiewicz, M, Drulis-Fajdasz, D, et al.. Targeting GSK3 signaling as a potential therapy of neurodegenerative diseases and aging. Expert Opin Ther Targets 2018;22:833–48. https://doi.org/10.1080/14728222.2018.1526925.Search in Google Scholar PubMed

48. Beaulieu, JM, Gainetdinov, RR, Caron, MG. The Akt-GSK-3 signaling cascade in the actions of dopamine. Trends Pharmacol Sci 2007a;28:166–72. https://doi.org/10.1016/j.tips.2007.02.006.Search in Google Scholar PubMed

49. Beaulieu, JM, Tirotta, E, Sotnikova, TD, Masri, B, Salahpour, A, Gainetdinov, RR, et al.. Regulation of Akt signaling by D2 and D3 dopamine receptors in vivo. J Neurosci 2007b;27:881–5. https://doi.org/10.1523/jneurosci.5074-06.2007.Search in Google Scholar PubMed PubMed Central

Received: 2021-01-10
Accepted: 2021-03-02
Published Online: 2021-05-07

© 2021 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Evidence implementation among complementary medicine practitioners: a meta-summary
  4. Phytochemical: a treatment option for heavy metal induced neurotoxicity
  5. The effects of curcumin-containing supplementations on inflammatory markers and lipid profiles in patients with chronic kidney diseases: a systematic review and meta-analysis of randomized controlled trials
  6. A systematic review on traditional medicinal Animal’s parts and products used for the treatment of respiratory tract disorders in Ethiopia
  7. Review on nutraceuticals: phase transition from preventive to protective care
  8. A study of effect of Centella asiatica on oxidative markers in the hippocampus of offsprings born to alcohol-fed pregnant rats and the correlation with their cognitive functions
  9. Anxiogenic and anxiolytic effects of memantine injected into the ventral hippocampus in male stressed mice
  10. Research Articles
  11. Comparison of antithyroid effects and hepatic complications of methimazole with catechin and its nanoencapsulation form in adult male rats
  12. Almond oil restores blood parameters, liver function, blood and liver antioxidants and DNA, and liver histology more efficiently than olive oil in favism
  13. Highly efficient microencapsulation of phytonutrients by fractioned cellulose using biopolymer complexation technology
  14. Ocimum basilicum alleviates blood glucose, lipid profile and iNOS in diabetes gestational rat model
  15. Blood pressure and blood sugar-lowering effects of purified gambir on diabetic hypertensive Wistar Kyoto rats
  16. Assessment of anti-inflammatory and antioxidant activity of quercetin–rutin blend (SophorOx™) – an invitro cell based assay
  17. Subchronic toxicological evaluation of EnXtra™ (standardised extract of Alpinia galanga rhizome) in rats
  18. Ficus glumosa Del. reduces phenylhydrazine-induced hemolytic anaemia and hepatic damage in Wistar rats
  19. Screening of anti-cancerous potential of classical Raudra rasa and modified Raudra rasa modified with hiraka bhasma (nanodiamond) through FTIR & LC-MS analysis
  20. Aqueous extract of Pedalium murex D. Royen ex L. leafy stem protects against lead induced testicular toxicity in Wistar rats
  21. Intrahippocampal co-administration of nicotine and O-acetyl-L-carnitine prevents the H-89-induced spatial learning deficits in Morris water maze
  22. Developmental effects of early-life stress on dopamine D2 receptor and proteins involved in noncanonical D2 dopamine receptor signaling pathway in the prefrontal cortex of male rats
  23. Probiotic administration enhanced antitrypanosomal effects of diminazene aceturate in dogs experimentally infected with Trypanosoma brucei brucei
  24. Acacia arabica (Lam.) Willd. On osteoblastogenesis, osteoblast proliferation, osteoclastic activity, and bone calcium mineralization
  25. GC-MS analysis of curculigo orchiodes and medicinal herbs with cytotoxic, hepatoprotective attributes of ethanolic extract from Indian origin
  26. Biochemical and histopathological evaluation of liver, kidney, and pancreas in normal Sprague Dawley rats administered aqueous extract of beetroot (Beta vulgaris)
  27. The effectiveness of emotional freedom techniques (EFT) on depression of postmenopausal women: a randomized controlled trial
  28. The formulation and efficacy of topical Dorema ammoniacum in treating Melasma: a randomized double-blind, placebo-controlled trial
  29. Impact of inhalation aromatherapy with Damask Rose (Rosa damascena) on stress, anxiety and hemodynamic parameters of patients undergoing coronary angiography: a single blind randomized clinical trial
  30. Hydro-alcoholic extract of Morus nigra reduces fasting blood glucose and HbA1c% in diabetic patients, probably via competitive and allosteric interaction with alpha-glucosidase enzyme; a clinical trial and in silico analysis
  31. Prophylactic management of radiation-induced mucositis using herbal mouthwash in patients with head and neck cancer: an assessor-blinded randomized controlled trial
  32. Implementation science in New Zealand naturopathic practice: a cross-sectional study
  33. Issues of mindfulness implementation for oncology caregivers
  34. Immediate effect of cold mud pack therapy on autonomic variables in primary hypertensive individuals: a randomized trial
  35. Effect of a Persian metabolic diet on the functional dyspepsia symptoms in patients with postprandial distress syndrome: a randomized, double-blind clinical trial
https://doi.org/10.1515/jcim-2020-0539
Keywords for this article
adolescence; dopamine; D2-receptor; early-life stress; GSK-3β; prefrontal cortex; rat

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Evidence implementation among complementary medicine practitioners: a meta-summary
  4. Phytochemical: a treatment option for heavy metal induced neurotoxicity
  5. The effects of curcumin-containing supplementations on inflammatory markers and lipid profiles in patients with chronic kidney diseases: a systematic review and meta-analysis of randomized controlled trials
  6. A systematic review on traditional medicinal Animal’s parts and products used for the treatment of respiratory tract disorders in Ethiopia
  7. Review on nutraceuticals: phase transition from preventive to protective care
  8. A study of effect of Centella asiatica on oxidative markers in the hippocampus of offsprings born to alcohol-fed pregnant rats and the correlation with their cognitive functions
  9. Anxiogenic and anxiolytic effects of memantine injected into the ventral hippocampus in male stressed mice
  10. Research Articles
  11. Comparison of antithyroid effects and hepatic complications of methimazole with catechin and its nanoencapsulation form in adult male rats
  12. Almond oil restores blood parameters, liver function, blood and liver antioxidants and DNA, and liver histology more efficiently than olive oil in favism
  13. Highly efficient microencapsulation of phytonutrients by fractioned cellulose using biopolymer complexation technology
  14. Ocimum basilicum alleviates blood glucose, lipid profile and iNOS in diabetes gestational rat model
  15. Blood pressure and blood sugar-lowering effects of purified gambir on diabetic hypertensive Wistar Kyoto rats
  16. Assessment of anti-inflammatory and antioxidant activity of quercetin–rutin blend (SophorOx™) – an invitro cell based assay
  17. Subchronic toxicological evaluation of EnXtra™ (standardised extract of Alpinia galanga rhizome) in rats
  18. Ficus glumosa Del. reduces phenylhydrazine-induced hemolytic anaemia and hepatic damage in Wistar rats
  19. Screening of anti-cancerous potential of classical Raudra rasa and modified Raudra rasa modified with hiraka bhasma (nanodiamond) through FTIR & LC-MS analysis
  20. Aqueous extract of Pedalium murex D. Royen ex L. leafy stem protects against lead induced testicular toxicity in Wistar rats
  21. Intrahippocampal co-administration of nicotine and O-acetyl-L-carnitine prevents the H-89-induced spatial learning deficits in Morris water maze
  22. Developmental effects of early-life stress on dopamine D2 receptor and proteins involved in noncanonical D2 dopamine receptor signaling pathway in the prefrontal cortex of male rats
  23. Probiotic administration enhanced antitrypanosomal effects of diminazene aceturate in dogs experimentally infected with Trypanosoma brucei brucei
  24. Acacia arabica (Lam.) Willd. On osteoblastogenesis, osteoblast proliferation, osteoclastic activity, and bone calcium mineralization
  25. GC-MS analysis of curculigo orchiodes and medicinal herbs with cytotoxic, hepatoprotective attributes of ethanolic extract from Indian origin
  26. Biochemical and histopathological evaluation of liver, kidney, and pancreas in normal Sprague Dawley rats administered aqueous extract of beetroot (Beta vulgaris)
  27. The effectiveness of emotional freedom techniques (EFT) on depression of postmenopausal women: a randomized controlled trial
  28. The formulation and efficacy of topical Dorema ammoniacum in treating Melasma: a randomized double-blind, placebo-controlled trial
  29. Impact of inhalation aromatherapy with Damask Rose (Rosa damascena) on stress, anxiety and hemodynamic parameters of patients undergoing coronary angiography: a single blind randomized clinical trial
  30. Hydro-alcoholic extract of Morus nigra reduces fasting blood glucose and HbA1c% in diabetic patients, probably via competitive and allosteric interaction with alpha-glucosidase enzyme; a clinical trial and in silico analysis
  31. Prophylactic management of radiation-induced mucositis using herbal mouthwash in patients with head and neck cancer: an assessor-blinded randomized controlled trial
  32. Implementation science in New Zealand naturopathic practice: a cross-sectional study
  33. Issues of mindfulness implementation for oncology caregivers
  34. Immediate effect of cold mud pack therapy on autonomic variables in primary hypertensive individuals: a randomized trial
  35. Effect of a Persian metabolic diet on the functional dyspepsia symptoms in patients with postprandial distress syndrome: a randomized, double-blind clinical trial
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 27.11.2025 from https://www.degruyterbrill.com/document/doi/10.1515/jcim-2020-0539/html
Scroll to top button