IJAR.2024.246
Type of Article: Original Research
Volume 13; Issue 1 (March 2025)
Page No.: 9118-9126
DOI: https://dx.doi.org/10.16965/ijar.2024.246
Neuroprotective Effects of Centella asiatica Against AlCl 3 and D-Galactose-Induced Astrocyte Activation and Hippocampal Neurodegeneration in Male Albino Wistar Rats
Thirupathirao. Vishnumukkala 1a,1b, Ravindra Kumar Boddeti 2, Prarthana Kalerammana Gopalakrishna 3, Barani Karikalan 4, Saravanan Jagadeesan5, Mohamad Taufik Hidayat B. Baharuldin6, Nurul Huda Mohd Nor 7, Mohamad Aris Mohd Moklas *8.
1a Ph.D Scholar, Department of Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia.
1b Lecturer, Anatomy Discipline, Human Biology Division, School of Medicine, IMU University, Kuala Lumpur, Malaysia. ORCiD: https://orcid.org/0000-0002-9517-3726
2 Associate Professor, Department of Anatomy, Parul Institute of Medical Sciences & Research, Faculty of Medicine, Parul University, Vadodara, Gujarat, India. ORCiD: https://orcid.org/0000-0003-0569-1472
3 Lecturer, Physiology Discipline, Human Biology division, School of Medicine, IMU University, Kuala Lumpur, Malaysia. ORCiD: https://orcid.org/0000-0002-1428-5305
4 Associate Professor, Department of Pathology, Faculty of Medicine, Bioscience and Nursing, MAHSA university, Bandar Saujana Putra, Selangor, Malaysia. ORCiD: https://orcid.org/0000-0002-5751-346X
5 Associate Professor, Department of Anatomy, School of Medicine, Taylors University, Lakeside Campus, Selangor, Malaysia. ORCiD: https://orcid.org/0000-0001-7389-7363
6 Professor, Department of Preclinical, Faculty of Medicine and Defence Health, National Defence University of Malaysia, Kuala Lumpur, Malaysia. ORCiD: https://orcid.org/0000-0003-4773-8531
7 Lecturer, Anatomy Unit, Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia. ORCiD: https://orcid.org/0000-0002-8136-5604
8 Professor, Anatomy Unit, Department of Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia. ORCiD: https://orcid.org/0000-0002-9282-129X
Corresponding Author: Prof. Dr. Mohamad Aris Bin Mohd Moklas. PhD (Nottingham University), Anatomy Unit, Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia.+603-97692783 E-Mail: aris@upm.edu.my
ABSTRACT
Background: Alzheimer’s disease (AD) a neurodegenerative disorder is a leading cause of dementia in the elderly population. The concurrent dosing of rats with aluminium chloride (AlCl3) and D-galactose (D-gal) is regarded an effective approach for developing an animal model to study AD. Centella asiatica (CA) demonstrates neuroprotective effects in both in vitro and in vivo studies. This research investigated the protective effects of CA against neurodegeneration of the hippocampus and activation of astrocytes in rats treated with AlCl3 and D-gal.
Materials and methods: Rats received AlCl3 at a dosage of 200 mg/kg body weight daily, D-gal at 60 mg/kg body weight daily, and CA at 100, 200, and 300 mg/kg body weight daily, in conjunction with donepezil at 1 mg/kg body weight daily, for a duration of 70 days. Following treatment, the brain tissue was fixed in 10% formalin for further histological analysis. Nissl staining was applied to examine the survival of CA2 neurons in the hippocampus, whereas Glial Fibrillary Acid Protein (GFAP) was employed to assess active astrocytes in the CA2 hippocampal area.
Results: The findings indicated that AlCl3 and D-gal could substantially harm the hippocampus CA2 pyramidal neurons in rats. Furthermore, it induced the activation of astrocytes in the rat hippocampus. Co-administration of CA at doses of 100mg, 200mg, and 300mg mitigated neurodegeneration and astrocyte activation in the hippocampus of the rats.
Conclusion: The findings indicate that CA may safeguard against morphological changes induced by AlCl3 and D-gal in rats. Molecular investigations are under underway to clarify the potential effects of CA.
Keywords: AlCl3, D-galactose, Neurodegeneration, Astrocytes, Centella asiatica, Hippocampus.
REFERENCES
[1]. Silva MVF, Loures C de MG, Alves LCV, de Souza LC, Borges KBG, Carvalho M das G. Alzheimer’s disease: risk factors and potentially protective measures. J Biomed Sci. 2019;26(1):33.
https://doi.org/10.1186/s12929-019-0524-y
PMid:31072403 PMCid:PMC6507104
[2]. Collaborators GD, Szoeke NE, Vollset C, Abbasi SE, Abd-Allah N. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990-2016: a systematic analysis for the Global Burden of Disease Study. Lancet Neurol. 2016; 18:88-106.
[3]. Ali, M. F., Ja’afar, N. I. S., Krishnan, T. G., Zulkifle, M. A. M., Khaidzir, N. K., Jamil, T. R., Aziz, A. F. A. Dementia awareness among elderly at risk for developing mild cognitive impairment: a cross-sectional study at a university-based primary care clinic. BMC Geriatrics. 2023; 23(1):496.
https://doi.org/10.1186/s12877-023-04230-4
PMid:37592221 PMCid:PMC10436505
[4]. Vishnumukkala T, Gopalakrishna PK, Jagadeesan S, Chiroma SM, Nor NHM, Baharuldin MTH, et al. Herbal medicine: A promising approach for the treatment of Alzheimer’s disease. Int J Ayurveda Pharma Res. 2024;142-50.
https://doi.org/10.47070/ijapr.v12i1.3103
[5]. García-Morales V, González-Acedo A, Melguizo-Rodríguez L, Pardo-Moreno T, Costela-Ruiz VJ, Montiel-Troya M, et al. Current understanding of the physiopathology, diagnosis and therapeutic approach to Alzheimer’s disease. Biomedicines. 2021;9(12):1910.
https://doi.org/10.3390/biomedicines9121910
PMid:34944723 PMCid:PMC8698840
[6]. Thirupathirao. Vishnumukkala, Prarthana Kalerammana Gopalakrishna, Barani Karikalan, Saravanan Jagadeesan, Mohamad Taufik Hidayat B. Baharuldin, Warren Thomas, Mohamad Aris Mohd Moklas. Protective Effect of Centella asiatica on AlCl3 and D-Galactose Induced Hepatotoxicity in Rats through the Alleviation of Oxidative Stress as Demonstrated by Histological Changes in Liver. Int J Anat Res 2023;11(4):8740-8747.
https://doi.org/10.16965/ijar.2023.204
[7]. Khan KA, Kumar N, Nayak PG, Nampoothiri M, Shenoy RR, Krishnadas N, et al. Impact of caffeic acid on aluminium chloride-induced dementia in rats: Caffeic acid and dementia. J Pharm Pharmacol. 2013;65(12):1745-52.
https://doi.org/10.1111/jphp.12126
PMid:24236984
[8]. Xue J-S, Li J-Q, Wang C-C, Ma X-H, Dai H, Xu C-B, et al. Dauricine alleviates cognitive impairment in Alzheimer’s disease mice induced by D-galactose and AlCl3 via the Ca2+/CaM pathway. Toxicol Appl Pharmacol. 2023;474(116613):116613.
https://doi.org/10.1016/j.taap.2023.116613
PMid:37414289
[9]. Aimone JB, Deng W, Gage FH. Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron. 2011;70(4):589-96.
https://doi.org/10.1016/j.neuron.2011.05.010
PMid:21609818 PMCid:PMC3240575
[10]. Prakash D, Gopinath K, Sudhandiran G. Fisetin enhances behavioral performances and attenuates reactive gliosis and inflammation during aluminum chloride-induced neurotoxicity. Neuromolecular Med. 2013;15(1):192-208.
https://doi.org/10.1007/s12017-012-8210-1
PMid:23315010
[11]. Junior AFS, Aguiar MSS, Junior OSC, Luana De Nazaré SS, Franco EC, Lima RR, et al. Hippocampal neuronal loss, decreased GFAP immunoreactivity and cognitive impairment following experimental intoxication of rats with aluminum citrate. Brain research. 2013;1491;23-33.
https://doi.org/10.1016/j.brainres.2012.10.063
PMid:23131585
[12]. Kaizer RR, Corrêa MC, Spanevello RM, Morsch VM, Mazzanti CM, Gonçalves JF, et al. Acetylcholinesterase activation and enhanced lipid peroxidation after long-term exposure to low levels of aluminum on different mouse brain regions. J Inorg Biochem. 2005;99(9):1865-70.
https://doi.org/10.1016/j.jinorgbio.2005.06.015
PMid:16055195
[13]. Shwe T, Pratchayasakul W, Chattipakorn N, Chattipakorn SC. Role of D-galactose-induced brain aging and its potential used for therapeutic interventions. Exp Gerontol. 2018; 101:13-36.
https://doi.org/10.1016/j.exger.2017.10.029
PMid:29129736
[14]. Vishnumukkala T, Gopalakrishna PK, Karikalan B, Thomas W, Jagadeesan S, Musa Chiroma S, et al. Centella asiatica ameliorates AlCl3 and D-galactose induced nephrotoxicity in rats via modulation of oxidative stress. Bioinformation. 2024;20(5):508-14.
https://doi.org/10.6026/973206300200508
PMid:39132239 PMCid:PMC11309103
[15]. Xue J-S, Li J-Q, Wang C-C, Ma X-H, Dai H, Xu C-B, et al. Dauricine alleviates cognitive impairment in Alzheimer’s disease mice induced by D-galactose and AlCl3 via the Ca2+/CaM pathway. Toxicol Appl Pharmacol. 2023;474(116613):116613.
https://doi.org/10.1016/j.taap.2023.116613
PMid:37414289
[16]. Aihaiti M, Shi H, Liu Y, Hou C, Song X, Li M, et al. Nervonic acid reduces the cognitive and neurological disturbances induced by combined doses of D-galactose/AlCl3 in mice. Food Sci Nutr. 2023;11(10):5989-98.
https://doi.org/10.1002/fsn3.3533
PMid:37823115 PMCid:PMC10563680
[17]. Haider S, Liaquat L, Ahmad S, Batool Z, Siddiqui RA, Tabassum S, et al. Naringenin protects AlCl3/D-galactose induced neurotoxicity in rat model of AD via attenuation of acetylcholinesterase levels and inhibition of oxidative stress. PLoS One. 2020;15(1):e0227631.
https://doi.org/10.1371/journal.pone.0227631
PMid:31945778 PMCid:PMC6964982
[18]. Prarthana Kalerammana Gopalakrishna S, Venkatesh R, Naik S, Sura VT. The Role of Astrocytes in Alzheimer’s disease. Int Res J Biological Sci. 2023;12(3):17-20.
[19]. De Bastiani MA, Bellaver B, Brum WS, Souza DG, Ferreira PCL, Rocha AS, et al. Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies. Brain Behav Immun. 2023; 110:175-84.
https://doi.org/10.1016/j.bbi.2023.03.001
PMid:36878332
[20]. Laabbar W, Abbaoui A, Elgot A, Mokni M, Amri M, Masmoudi-Kouki O, et al. Aluminum induced oxidative stress, astrogliosis and cell death in rat astrocytes, is prevented by curcumin. J Chem Neuroanat. 2021;112(101915):101915.
https://doi.org/10.1016/j.jchemneu.2020.101915
PMid:33370573
[21]. Jeong H-K, Ji K-M, Min K-J, Choi I, Choi D-J, Jou I, et al. Astrogliosis is a possible player in preventing delayed neuronal death. Mol Cells. 2014;37(4):345-55.
https://doi.org/10.14348/molcells.2014.0046
PMid:24802057 PMCid:PMC4012084
[22]. Sun B, Wu L, Wu Y, Zhang C, Qin L, Hayashi M, et al. Therapeutic Potential of Centella asiatica and Its Triterpenes: A Review. Front Pharmacol. 2020; 11:568032.
https://doi.org/10.3389/fphar.2020.568032
PMid:33013406 PMCid:PMC7498642
[23]. Jagadeesan S, Gopalakrishna PK, Sura S, Karikalan B, Dandala KCR, Ravindranadh G, et al. Prevention of neuronal damage in brains of chronic stress-induced Male Wistar rats administering Centella asiatica (L) urban. J Anat Soc India. 2024;73(3):204-13.
https://doi.org/10.4103/jasi.jasi_80_24
[24]. Xu M-F, Xiong Y-Y, Liu J-K, Qian J-J, Zhu L, Gao J. Asiatic acid, a pentacyclic triterpene in Centella asiatica, attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Y cells. Acta Pharmacol Sin. 2012;33(5):578-87.
https://doi.org/10.1038/aps.2012.3
PMid:22447225 PMCid:PMC4010358
[25]. Rather A, Justin-Thenmozhi M, Manivasagam A, Saravanababu T, Guillemin C, Essa GJ. Asiatic acid attenuated aluminum chloride-induced tau pathology, oxidative stress and apoptosis via AKT/GSK-3β signaling pathway in wistar rats. Neurotoxicity research. 2019; 35:955-68.
https://doi.org/10.1007/s12640-019-9999-2
PMid:30671870
[26]. Insausti, R., Muñoz-López, M., & Insausti, A. M. The CA2 hippocampal subfield in humans: A review. Hippocampus.2023;33(6), 712-729.
https://doi.org/10.1002/hipo.23547
PMid:37204159
[27]. Ding, L., Chen, H., Diamantaki, M., Coletta, S., Preston-Ferrer, P., & Burgalossi, A. Structural Correlates of CA2 and CA3 Pyramidal Cell Activity in Freely Moving Mice. The Journal of neuroscience: the official journal of the Society for Neuroscience.2020;40(30):5797-5806.
https://doi.org/10.1523/JNEUROSCI.0099-20.2020
PMid:32554511 PMCid:PMC7380973
[28]. Lehr, A. B., Kumar, A., Tetzlaff, C., Hafting, T., Fyhn, M., & Stöber, T. M. CA2 beyond social memory: Evidence for a fundamental role in hippocampal information processing. Neuroscience and biobehavioral reviews.2021;126, 398-412.
https://doi.org/10.1016/j.neubiorev.2021.03.020
PMid:33775693
[29]. Piskorowski, R. A., & Chevaleyre, V. Hippocampal area CA2: interneuron disfunction during pathological states. Frontiers in neural circuits.2023;17:1181032.
https://doi.org/10.3389/fncir.2023.1181032
PMid:37180763 PMCid:PMC10174260
[30]. Piskorowski, R. A., Nasrallah, K., Diamantopoulou, A., Mukai, J., Hassan, S. I., Siegelbaum, S. A., Gogos, J. A., & Chevaleyre, V. Age-Dependent Specific Changes in Area CA2 of the Hippocampus and Social Memory Deficit in a Mouse Model of the 22q11.2 Deletion Syndrome. Neuron. 2016;89(1), 163-176.
https://doi.org/10.1016/j.neuron.2015.11.036
PMid:26748091 PMCid:PMC4706988
[31]. Wilson, D. M., 3rd, Cookson, M. R., Van Den Bosch, L., Zetterberg, H., Holtzman, D. M., & Dewachter, I. Hallmarks of neurodegenerative diseases. Cell.2023; 186(4), 693-714.
https://doi.org/10.1016/j.cell.2022.12.032
PMid:36803602
[32]. Sheppard, O., & Coleman, M. Alzheimer’s Disease: Etiology, Neuropathology and Pathogenesis. In X. Huang (Ed.), Alzheimer’s Disease: Drug Discovery. Exon Publications.2020;1-22.
https://doi.org/10.36255/exonpublications.alzheimersdisease.2020.ch1
PMCid:PMC6889002
[33]. Zhang, H., Wang, X., Xu, P. et al. Tolfenamic acid inhibits GSK-3β and PP2A mediated tau hyperphosphorylation in Alzheimer’s disease models. J Physiol Sci.2020;70:29.
https://doi.org/10.1186/s12576-020-00757-y
PMid:32517647 PMCid:PMC10717460
[34]. Farhani, N. I. B. R., Chiroma, S. M., Mohamad, T. A. S. T., & Mohd Moklas, M. A. Centella asiatica L. Urban protects against cognitive dysfunction in alluminum chloride-induced neurotoxicity in rats via inhibition of acetylcholinesterase level. Egyptian Journal of Basic and Applied Sciences.2022;10(1):33-44.
https://doi.org/10.1080/2314808X.2022.2139114
[35]. Wong, J. H., Muthuraju, S., Reza, F., Senik, M. H., Zhang, J., Mohd Yusuf Yeo, N. A. B., Chuang, H. G., Jaafar, H., Yusof, S. R., Mohamad, H., Tengku Muhammad, T. S., Ismail, N. H., Husin, S. S., & Abdullah, J. M. Differential expression of entorhinal cortex and hippocampal subfields α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors enhanced learning and memory of rats following administration of Centella asiatica. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.2019;110:168-180.
https://doi.org/10.1016/j.biopha.2018.11.044
PMid:30469081
[36]. Di Benedetto, G., Burgaletto, C., Bellanca, C. M., Munafò, A., Bernardini, R., & Cantarella, G. Role of Microglia and Astrocytes in Alzheimer’s Disease: From Neuroinflammation to Ca2+ Homeostasis Dysregulation. Cells.2022;11(17):2728.
https://doi.org/10.3390/cells11172728
PMid:36078138 PMCid:PMC9454513
[37]. Zhang, W., Xiao, D., Mao, Q. et al. Role of neuroinflammation in neurodegeneration development. Sig Transduct Target Ther.2023;8:267.
https://doi.org/10.1038/s41392-023-01486-5
PMid:37433768 PMCid:PMC10336149
[38]. Yang, K.; Liu, Y.; Zhang, M. The Diverse Roles of Reactive Astrocytes in the Pathogenesis of Amyotrophic Lateral Sclerosis. Brain Sci. 2024;14:158.
https://doi.org/10.3390/brainsci14020158
PMid:38391732 PMCid:PMC10886687
[39]. Wong, J. H., Barron, A. M., & Abdullah, J. M. Mitoprotective Effects of Centella asiatica (L.) Urb.: Anti-Inflammatory and Neuroprotective Opportunities in Neurodegenerative Disease. Frontiers in pharmacology.2021;12:687935.
https://doi.org/10.3389/fphar.2021.687935
PMid:34267660 PMCid:PMC8275827
[40]. Sun, S., Gu, Y., Wang, J., Chen, C., Han, S., & Che, H. Effects of Fatty Acid Oxidation and Its Regulation on Dendritic Cell-Mediated Immune Responses in Allergies: An Immunometabolism Perspective. Journal of immunology research, 2021:7483865.
https://doi.org/10.1155/2021/7483865
PMid:34423053 PMCid:PMC8376428
[41]. Wculek, S. K., Heras-Murillo, I., Mastrangelo, A., Mañanes, D., Galán, M., Miguel, V., Curtabbi, A., Barbas, C., Chandel, N. S., Enríquez, J. A., Lamas, S., & Sancho, D. Oxidative phosphorylation selectively orchestrates tissue macrophage homeostasis. Immunity, 2023;56(3), 516-530.e9.
https://doi.org/10.1016/j.immuni.2023.01.011
PMid:36738738