Gallic Acid: A Potential Therapeutic Agent for Managing Diabetes-Associated Neuroinflammation and Cognitive Decline
DOI:
https://doi.org/10.47081/njn2025.16.1/001Keywords:
Gallic acid, Diabetes Mellitus, Neuroinflammation, Cognitive declineAbstract
Recent studies have implicated diabetes as a risk factor for neuroinflammation and cognitive decline, increasing the likelihood of dementia and other neurodegenerative disorders. Gallic acid, a polyphenolic compound extracted from gallnuts, is being studied for its possible therapeutic effects in glucose-related disorders. This study aimed to explore the potential of gallic acid as a therapeutic agent for managing diabetes-associated neuroinflammation and cognitive dysfunction. Thirty-two male Wistar rats used in this experiment were randomly divided into four groups: normal control, diabetic, and two groups receiving gallic acid at doses of 50 mg/kg and 100 mg/kg. The diabetic and gallic acid groups received 65mg/kg b.w. streptozotocin intraperitoneally and were subsequently treated with gallic acid. The open field test was used to assess long-term recognition memory, while brain tissue was collected for histology and biochemical analyses. Gallic acid treatment at a dose of 100mg/kg significantly improved habituation scores (p<0.05) and discrimination indices (p<0.05) in diabetic rats. Also, treatment with gallic acid prevented neuronal death and microglial depletion caused by diabetes, with mild microglial activation in the cerebral cortex. Furthermore, gallic acid treatment reduced neuroinflammation in a dose-dependent manner, characterised by decreased (p<0.05) interleukin-6 at 50 mg/kg and 100 mg/kg) and tumour necrosis factor-alpha levels (p<0.05) at 50 mg/kg and 100 mg/kg. The study found that gallic acid significantly protected cognitive function and reduced neuroinflammation in diabetic male Wistar rats. These findings suggest that gallic acid may serve as a therapeutic agent for managing diabetes-associated neuroinflammation and cognitive decline.
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Adebiyi, O., Adigun, K., David-Odewumi, P., Akindele, U. and Olayemi, F. (2022) Gallic and ascorbic acids supplementation alleviate cognitive deficits and neuropathological damage exerted by cadmium chloride in Wistar rats. Sci Rep. 12(1):14426. doi:10.1038/s41598-022-18432-0
Adefegha, S.A., Oboh, G., Ejakpovi, I.I. and Oyeleye, S.I. (2015) Antioxidant and antidiabetic effects of gallic and protocatechuic acids: a structure–function perspective. Comp Clin Pathol. 24:1579–1585.
Akkerman, S., Blokland, A., Reneerkens, O., van Goethem, N.P., Bollen, E., Gijselaers, H.J., et al. (2012) Object recognition testing: methodological considerations on exploration and discrimination measures. Behav Brain Res. 232(2):335–347. doi:10.1016/j.bbr.2012.03.022
Al-Sayyar, A., Hammad, M.M., Williams, M.R., Al-Onaizi, M., Abubaker, J. and Alzaid, F. (2023) Neurotransmitters in type 2 diabetes and the control of systemic and central energy balance. Metabolites. 13(3):384. doi:10.3390/met abo13030384
Antunes, M. and Biala, G. (2012) The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process. 13(2):93-110. doi:10.1007/ s10339-011-0430-z
Bancroft, J.D. and Layton, C. (2013) The hematoxylins and eosin. In: Bancroft's Theory and Practice of Histological Techniques. Elsevier. pp. 173-186). doi:10.1016/B978-0-7020-4226-3.00010-X
Barbiellini, A.C., Fayosse, A., Dumurgier, J., Machado-Fragua, M.D., Tabak, A.G., van Sloten, T., et al. (2021) Association between age at diabetes onset and subsequent risk of dementia. JAMA. 325:1640–1649. doi: 10.3390/metabo13030384
Bhuia, M.S., Rahaman, M.M., Islam, T., Bappi, M.H., Sikder, M.I., Hossain, K.N., et al. (2023) Neurobiological effects of gallic acid: current perspectives. Chin Med. 18(1):27. doi:10.1186/s13020-023-00735-7
Chao, J., Cheng, H.Y., Chang, M.L., Huang, S.S., Liao, J.W., Cheng, Y.C., et al. (2021) Gallic acid ameliorated impaired lipid homeostasis in a mouse model of high-fat diet-and streptozotocin-induced NAFLD and diabetes through improvement of β-oxidation and ketogenesis. Front Pharmacol. 11:606759. doi:10.3389/fphar.2020. 606759
Chao, J., Huo, T.I., Cheng, H.Y., Tsai, J.C., Liao, J.W., Lee, M.S., et al. (2014) Gallic acid ameliorated impaired glucose and lipid homeostasis in high fat diet-induced NAFLD mice. PLoS One. 9(2):e96969. doi:10.1371/journal. pone.0096969
Chatterjee, S., Khunti, K. and Davies, M.J. (2017) Type 2 diabetes. Lancet. 389:2239–2251.
Chen, X., Famurewa, A.C., Tang, J., Olatunde, O.O. and Olatunji, O.J. (2021) Hyperoside attenuates neuroinflamma tion, cognitive impairment and oxidative stress via suppressing TNF-α/NF-κB/caspase-3 signaling in type 2 diabetes rats. Nutr Neurosci. 25(8): 1774–1784. doi:10.1080/1028415X.2021.1901047
Chu, S., Junfei, G., Liang, F., Liu, J., Zhang, M., Jia, X., et al. (2024) Ginsenoside Rg5 improves cognitive dysfunction and beta-amyloid deposition in STZ-induced memory impaired rats via attenuating neuroinflammatory responses. Int Immunopharmacol. 19(2):317–326. doi:10.1016/j.intimp .2014.01.0
de Oliveira, L.S., Thomé, G.R., Lopes, T.F., Reichert, K.P., de Oliveira, J.S., da Silva Pereira, A., et al. (2016) Effects of gallic acid on delta - aminolevulinic dehydratase activity and in the biochemical, histological and oxidative stress parameters in the liver and kidney of diabetic rats. Biomed Pharmacother. 84:1291-1299. doi:10.1016/j.biopha.2016.1 0.021
Díaz, A., Muñoz, G., Caporal-Hernandez, K. and Vázquez-Roque, R.A. (2020) Gallic acid improves recognition memory and decreases oxidative-inflammatory damage in the rat hippocampus with metabolic syndrome. Synapse. 75(2):e22186. doi:10.1002/syn.22186
Dilworth, L., Facey, A. and Omoruyi, F. (2021) Diabetes mellitus and its metabolic complications: the role of adipose tissues. Int J Mol Sci. 22(14):7644. doi:10.3390/ ijms22147644.
Esmaeili, M.H., Enayati, M., Abkenar, F.K., Ebrahimian, F. and Salari, A.A. (2020) Glibenclamide mitigates cognitive impairment and hippocampal neuroinflammation in rats with type 2 diabetes and sporadic Alzheimer-like disease. Behav Brain Res. 379:112359. doi:10.1016/j.bbr.2019. 112359
Ferk, F., Kundi, M., Brath, H., Szekeres, T., Al-Serori, H., Mišík, M., et al, (2018) Gallic acid improves health-associated biochemical parameters and prevents oxidative damage of DNA in type 2 diabetes patients: Results of a placebo-controlled pilot study. Mol Nutr Food Res. 62:1700482. doi:10.1002/mnfr.201700482.
Gaskin, S., Tardif, M., Cole, E., Piterkin, P., Kayello, L. and Mumby, D.G. (2010) Object familiarization and novel-object preference in rats. Behav Proc. 83:61–71. doi: 10.1016/j.beproc.2009.10.003
Gąssowska-Dobrowolska, M., Chlubek, M., Kolasa, A., Tomasiak, P., Korbecki, J., Skowrońska, K., et al. (2023) Microglia and astroglia - The potential role in neuroinflammation induced by pre- and neonatal exposure to lead (Pb). Int J Mol Sci. 24(12):9903. doi:10.3390/ijms24129 903
Grote, C.W., Groover, A.L., Ryals, J.M., Geiger, P.C., Feldman, E.L. and Wright, D.E. (2013) Peripheral nervous system insulin resistance in ob/ob mice. Acta Neuropathol. Commun. 1:15. doi:10.1186/2051-5960-1-15
Hasanein, P. and Shahidi, S. (2011). Effects of hypericum perforatum extract on diabetes-induced learning and memory impairment in rats. Phytother Res. 25:544-549. doi:10.1002/ptr.3298
Inzucchi, S.E. (2013) Diagnosis of diabetes. N Engl J Med. 368:193. doi:10.1056/NEJMc1212738
Isik, S., Yeman, K.B., Akbayir, R., Seyhali, R. and Arpaci, T. (2023) Microglia mediated neuroinflammation in parkinson's disease. Cells. 12(7):1012. doi:10.3390/cells 12071012
Jinrong, B., Yunsen, Z., Ce, T., Ya, H., Xiaopeng A., Chen, X., et al. (2021) Gallic acid: Pharmacological activities and molecular mechanisms involved in inflammation-related diseases, Biomed Pharmacother. 133:110985. doi:10.10 16/j.biopha.2020.110985
Kahkeshani, N., Farzaei, F., Fotouhi, M., Alavi, S.S., Bahramsoltani, R., Naseri, R., et al. (2019) Pharmacological effects of gallic acid in health and diseases: A mechanistic review. Iran J Basic Med Sci. 22:225–237. doi:10.22038/ijb ms.2019.32806.7897
Karas, D., Ulrichová, J. and Valentová, K. (2017) Galloylation of polyphenols alters their biological activity. , Food Chem Toxicol. 105:223-240. doi:10.1016/j.fct. 2017.04.021
Kempuraj, D., Thangavel, R., Natteru, P.A., Selvakumar, G.P., Saeed, D., Zahoor, H., et al. (2016) Neuroinflammation induces neurodegeneration. J Neurol Neurosurg Spine. 1:1003.
Kinattingal, N., Mehdi, S., Undela, K., Wani, SUD., Almuqbil, M., Alshehri, S., et al. (2023) Prevalence of cognitive decline in type 2 diabetes mellitus patients: a real-world cross-sectional study in Mysuru, India. J Pers Med. 13(3):524. doi:10.3390/jpm13030524
Kwon, H.S. and Koh, SH. (2020) Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener. 9:42. doi:10.1186/s40 035-020-00221-2
Lueptow, L.M. (2017) Novel object recognition test for the investigation of learning and memory in mice. J Vis Exp. (126):55718. doi:10.3791/55718
Luna, R., Talanki M.R., Bollu, B., Jhaveri, S., Avanthika, C., Reddy, N., et al. (2021) A comprehensive review of neuronal changes in diabetics. Cureus. 13(10):e19142. doi:10.7759/cureus.19142
Mansouri, M.T., Farbood, Y., Sameri, M.J., Sarkaki, A., Naghizadeh, B. and Rafeirad, M. (2013) Neuroprotective effects of oral gallic acid against oxidative stress induced by 6-hydroxydopamine in rats. Food Chem. 138(2-3):1028-1033. doi:10.1016/j.foodchem.2012.11.022
National Center for Biotechnology Information (2024) PubChem Compound Summary for CID 370, Gallic Acid. Retrieved in July 11, 2024 from https://pubchem.ncbi.nlm.nih.gov/compound/Gallic-Acid.
National Research Council (2011) Guide for the Care and Use of Laboratory Animals: Eighth Edition. The National Academies Press. Washington, DC.
Obafemi, T.O., Jaiyesimi, K.F., Olomola, A.A., Olasehinde, O.R., Olaoye, O.A., Adewumi, F.D., et al. (2021) Combined effect of metformin and gallic acid on inflammation, antioxidant status, endoplasmic reticulum (ER) stress and glucose metabolism in fructose-fed streptozotocin-induced diabetic rats. Toxicol Rep. 8:1419-1427. doi:10.1016/j.tox rep.2021.07.011
Oboh, G., Ogunsuyi, O.B., Ogunbadejo, M.D. and Adefegha, S.A. (2016) Influence of gallic acid on α-amylase and α-glucosidase inhibitory properties of acarbose. J Food Drug Anal. 24(3):627-634. doi:10.1016/ j.jfda.2016.03.003
Ojo, O.A., Rotimi, D.E., Ojo, A.B., Ogunlakin, A.D. and Ajiboye, B.O. (2023) Gallic acid abates cadmium chloride toxicity via alteration of neurotransmitters and modulation of inflammatory markers in Wistar rats. Sci Rep. 13(1):1577. doi:10.1038/s41598-023-28893-6
Patel, S.S. and Goyal, R.K. (2011) Cardioprotective effects of gallic acid in diabetes-induced myocardial dysfunction in rats. Pharmacognosy Res. 3(4):239-245. doi:10.4103/0974 -8490.89743
Punithavathi, V.R., Stanely, M.P.P., Kumar, M.R. and Selvakumari, C.J (2011) Protective effects of gallic acid on hepatic lipid peroxide metabolism, glycoprotein components and lipids in streptozotocin-induced type II diabetic Wistar rats. J Biochem Mol Toxicol 25:68–76.
Rahimifard, M., Baeeri, M., Bahadar, H., Moini-Nodeh, S., Khalid, M., Haghi-Aminjan, H., et al, (2020) Therapeutic effects of gallic acid in regulating senescence and diabetes: an vitro study. Molecules. 25(24):5875. doi:10.3 390/molecules25245875
Reckziegel, P., Dias, V.T., Benvegnú, D.M., Boufleur, N., Barcelos, R.C.S., Segat, H.J., et al. (2016) Antioxidant protection of gallic acid against toxicity induced by Pb in blood, liver and kidney of rats. Toxicol Rep. 3:351-356. doi: 10.1016/j.toxrep.2016.02.005
Rojas-Carranza, C.A., Bustos-Cruz, R.H., Pino-Pinzon, C.J., Ariza-Marquez, Y.V., Gomez-Bello, R.M. and Canadas-Garre, M. (2018) Diabetes-related neurological implications and pharmacogenomics. Curr Pharm Des. 24(15):1695-1710. doi:10.2174/138161282366617031716 5350
Ruud, J., Steculorum, S.M. and Brüning, J.C. (2017) Neuronal control of peripheral insulin sensitivity and glucose metabolism. Nat. Commun. 8:15259. doi: 10.1038/ncomms15259
Sadeghi, A., Hami, J., Razavi, S., Esfandiary, E. and Hejazi, Z. (2016) The effect of diabetes mellitus on apoptosis in hippocampus: cellular and molecular aspects. Int J Prev Med. 7:57. doi:10.4103/2008-7802.178531
Sandireddy, R., Yerra, V.G., Areti, A., Komirishetty, P. and Kumar, A. (2014) Neuroinflammation and oxidative stress in diabetic neuropathy: futuristic strategies based on these targets. Int J Endocrinol. 2014:674987. doi:10.1155/2014/ 674987
Seaquist, E.R. (2010) The final frontier: how does diabetes affect the brain? Diabetes. 59(1):4–5.
Sebastian, M.J., Khan, S.K., Pappachan, J.M. and Jeeyavudeen, M.S. (2023) Diabetes and cognitive function: An evidence-based current perspective. World J Diabetes. 14(2):92-109. doi:10.4239/wjd.v14.i2.92
Selman, A., Burns, S., Reddy, A.P., Culberson, J. and Reddy, P.H. (2021) The role of obesity and diabetes in dementia. Int J Mol Sci. 23(16):9267. doi:10.3390/ ijms23169267
Struck, M.B., Andrutis, K.A., Ramirez, H.E. and Battles, A.H. (2011) Effect of a short-term fast on ketamine-xylazine anesthesia in rats. J Am Assoc Lab Anim Sci. 50(3):344-348.
Sun, J., Li, Y-Z., Ding, Y-H. Sun, J., Li, Y.Z., Ding, Y.H., et al. (2014) Neuroprotective effects of gallic acid against hypoxia/reoxygenation-induced mitochondrial dysfunctions in vitro and cerebral ischemia/reperfusion injury in vivo. Brain. Res. 1589:126–139. doi:10.1016/j.brainres.2014.09. 039
Tsalamandris, S., Antonopoulos, A.S., Oikonomou, E., Papamikroulis, G.A., Vogiatzi, G., Papaioannou, S., et al. (2019) The role of inflammation in diabetes: current concepts and future perspectives. Eur Cardiol. (1):50-59. doi: 10.15420/ecr.2018.33.1
Variya, B.C., Bakrania, A.K. and Patel, S.S. (2020) Antidiabetic potential of gallic acid from Emblica officinalis: Improved glucose transporters and insulin sensitivity through PPAR-γ and Akt signaling. Phytomedicine. 73:152906. doi:10.1016/j.phymed.2019.152906
Vincent, A.M., Brownlee, M. and Russell, J.W. (2002) Oxidative stress and programmed cell death in diabetic neuropathy. Ann N Y Acad Sci. 959:368-383. doi: 10.1111/j.1749-6632.2002.tb02108.x
Wang, W.Y., Tan, M.S., Yu, J.T. and Tan, L. (2015) Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. Ann Transl Med. 3(10):136. doi: 10.3978/j.issn.2305-5839.2015.03.49
Wondmkun, Y.T. (2020) Obesity, insulin resistance, and type 2 diabetes: associations and therapeutic implications. Diabetes Metab Syndr Obes. 13:3611-3616. doi:10.2147/D MSO.S275898
Xu, Y., Tang, G., Zhang, C., Wang, N., and Feng, Y. (2021) Gallic acid and diabetes mellitus: its association with oxidative stress. Molecules. 26(23):7115. doi:10.3390/ molecules26237115.
Xue, M., Xu, W., Ou, Y.N., Cao, X.P., Tan, M.S., Tan, L., et al. (2019) Diabetes mellitus and risks of cognitive impairment and dementia: A systematic review and meta-analysis of 144 prospective studies. Ageing Res Rev. 55:100944. doi:10.1016/j.arr.2019.100944
Yu, M., Chen, X., Liu, J, Ma, Q., Zhuo, Z., Chen, H., et al. (2019) Gallic acid disruption of Aβ1–42 aggregation rescues cognitive decline of APP/PS1 double transgenic mouse. Neurobiol Dis. 124:67–80. doi:10.1016/j.nbd.2018. 11.009
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