Effects of Tualang Honey Pre-Treatment on Cerebellar and Striatal Neuronal Changes and Excitatory Amino Acid Transporter-2 (EAAT2) Expression Following Kainic Acid Exposure in Rats http://www.doi.org/10.26538/tjnpr/v8i1.22
Article Sidebar
Main Article Content
Abstract
Excitatory amino acid transporter-2 (EAAT2) is the predominant glutamate transporter that helps in maintaining low extracellular glutamate levels in the brain. Defect in EAAT2 causes impaired clearance and accumulation of this excitatory neurotransmitter, leading to excitotoxicity and neuronal cell death. The cerebellum and striatum play an important role in motor functions. This study aimed to evaluate the effects of Tualang honey (TH) on cerebellar and striatal neuronal changes as well as EAAT2 expression following kainic acid (KA) exposure in rats. Male Sprague-Dawley rats (n=48) were divided into four groups depending on the respective treatment. Each group was further divided into two subgroups based on time-point of sacrifice at 24-hour or at 5-days after KA injection. The rats were initially treated orally with distilled water, TH (1.0 g/kg) or topiramate (40 mg/kg), 12-hourly for five times. Then, the rats were injected with saline or KA (15 mg/kg) 30 minutes after the fifth oral dose. Before the rats were sacrificed, an open field test was conducted. Locomotor activity significantly increased in all KA-injected groups 5 days after KA administration. TH pre-treatment significantly reduced cerebellar neuronal death 5 days after KA injection. TH pre-treatment also showed to reduce KA-induced loss of striatal neurons 24 hours after KA injection as well as increases EAAT2 expression in 24 hours and 5 days groups. These results imply that pre-treatment with TH may mitigate the KA-induced excitotoxicity in the cerebellum and striatum partly via modulation of EAAT2 expression.
Article Details
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
References
Moujalled D, Strasser A, Liddell JR. Molecular mechanisms of cell death in neurological diseases. Cell Death Differ. 2021;28(7):2029–2044. https://doi.org/10.1038/s41418-021-00814-y
Andreone BJ, Larhammar M, Lewcock JW. Cell death and neurodegeneration. Cold Spring Harb Perspect Biol. 2020;12(2):a036434. https://doi.org/10.1101/cshperspect.a036434
Todd AC, Hardingham GE. The Regulation of Astrocytic Glutamate Transporters in Health and Neurodegenerative Diseases. Int J Mol Sci. 2020; 21(24):9607. https://doi.org/10.3390/ijms21249607
Green JL, dos Santos WF, Fontana ACK. Role of glutamate excitotoxicity and glutamate transporter EAAT2 in epilepsy: Opportunities for novel therapeutics development. Biochem Pharmacol. 2021;193:114786. https://doi.org/10.1016/j.bcp.2021.114786
Malik AR, Willnow TE. Excitatory Amino Acid Transporters in Physiology and Disorders of the Central Nervous System. Int J Mol Sci. 2019;20(22):5671. https://doi.org/10.3390/ijms20225671
Hotz AL, Jamali A, Rieser NN, Niklaus S, Aydin E, Myren-Svelstad S, Lalla L, Jurisch-Yaksi N, Yaksi E, Neuhauss SCF. Loss of glutamate transporter eaat2a leads to aberrant neuronal excitability, recurrent epileptic seizures, and basal hypoactivity. Glia. 2022;70(1):196–214. https://doi.org/10.1002/glia.24106
Qu Q, Zhang W, Wang J, Mai D, Ren S, Qu S, Zhang Y. Functional investigation of SLC1A2 variants associated with epilepsy. Cell Death Dis. 2022;13(12):1063. https://doi.org/10.1038/s41419-022-05457-6
Ramandi D, Salmani ME, Moghimi A, Lashkarbolouki T, Fereidoni M. Pharmacological upregulation of GLT-1 alleviates the cognitive impairments in the animal model of temporal lobe epilepsy. PLoS One. 2021;16(1):e0246068. https://doi.org/10.1371/journal.pone.0246068
Sha L, Li G, Zhang X, Lin Y, Qiu Y, Deng Y, Zhu W, Xu Q. Pharmacological induction of AMFR increases functional EAAT2 oligomer levels and reduces epileptic seizures in mice. JCI Insight. 2022;7(15):e160247. https://doi.org/10.1172/jci.insight.160247
Rusina E, Bernard C, Williamson A. The Kainic Acid Models of Temporal Lobe Epilepsy. eNeuro. 2021;8(2):ENEURO.0337-20.2021. https://doi.org/10.1523/ENEURO.0337-20.2021
Riljak V, Marešová D, Pokorný J, Jandová K. Subconvulsive dose of kainic acid transiently increases the locomotor activity of adult Wistar rats. Physiol Res. 2015;64(2):263–267. https://doi.org/10.33549/physiolres.932793
Zheng X-Y, Zhang H-L, Luo Q, Zhu J. Kainic Acid-Induced Neurodegenerative Model: Potentials and Limitations. J Biomed Biotechnol. 2011;2011:457079. https://doi.org/10.1155/2011/457079
Kandashvili M, Gamkrelidze G, Tsverava L, Lordkipanidze T, Lepsveridze E, Lagani V, Burjanadze M, Dashniani M, Kokaia M, Solomonia R. Myo‐Inositol Limits Kainic Acid‐Induced Epileptogenesis in Rats. Int J Mol Sci. 2022;23(3):1198. https://doi.org/10.3390/ijms23031198
Lintunen M, Sallmen T, Karlstedt K, Panula P. Transient changes in the limbic histaminergic system after systemic kainic acid-induced seizures. Neurobiol Dis. 2005;20(1):155–169. https://doi.org/https://doi.org/10.1016/j.nbd.2005.02.007
Sperk G, Wieser R, Widmann R, Singer EA. Kainic acid induced seizures: Changes in somatostatin, substance P and neurotensin. Neuroscience. 1986;17(4):1117–1126. https://doi.org/10.1016/0306-4522(86)90081-3
Guevara BH, Torrico F, Hoffmann IS, Cubeddu LX. Lesion of caudate-putamen interneurons with kainic acid alters dopamine and serotonin metabolism in the olfactory tubercle of the rat. Cell Mol Neurobiol. 2002;22(5–6):835–844. https://doi.org/10.1023/a:1021829629357
Bostan AC, Strick PL. The basal ganglia and the cerebellum: nodes in an integrated network. Nat Rev Neurosci. 2018;19(6):338–350. https://doi.org/10.1038/s41583-018-0002-7
Centonze D, Rossi S, De Bartolo P, De Chiara V, Foti F, Musella A, Mataluni G, Rossi S, Bernardi G, Koch G, Petrosini L. Adaptations of glutamatergic synapses in the striatum contribute to recovery from cerebellar damage. Eur J Neurosci. 2008;27(8):2188–2196. https://doi.org/10.1111/j.1460-9568.2008.06182.x
El-Seedi HR, Khalifa SAM, El-Wahed AA, Gao R, Guo Z, Tahir HE, Zhao C, Du M, Farag MA, Musharraf SG, Abbas G. Honeybee products: An updated review of neurological actions. Trends Food Sci Technol. 2020;101:17–27. https://doi.org/10.1016/j.tifs.2020.04.026
Weis WA, Ripari N, Conte FL, Honorio M da S, Sartori AA, Matucci RH, Sforcin JM. An overview about apitherapy and its clinical applications. Phytomedicine Plus. 2022;2(2):100239. https://doi.org/10.1016/j.phyplu.2022.100239
Azman KF, Aziz CB, Zakaria R, Ahmad AH, Shafin N, Ismail CA. Tualang Honey: A Decade of Neurological Research. Molecules. 2021;26(17):5424. https://doi.org/10.3390/molecules26175424
Mohd Sairazi NS, K.N.S. S, Asari MA, Mummedy S, Muzaimi M, Sulaiman SA. Effect of tualang honey against KA-induced oxidative stress and neurodegeneration in the cortex of rats. BMC Complement Altern Med. 2017;17(1):31. https://doi.org/10.1186/s12906-016-1534-x
Mohd Sairazi NS, K.N.S. S, Muzaimi M, Swamy M, Sulaiman SA. Tualang honey attenuates kainic acid-induced oxidative stress in rat cerebellum and brainstem. Int J Pharm Pharm Sci. 2017;9:155. https://doi.org/10.22159/ijpps.2017v9i12.21084
Mohd Sairazi NS, Sirajudeen KNS, Muzaimi M, Mummedy S, Asari MA, Sulaiman SA. Tualang Honey Reduced Neuroinflammation and Caspase-3 Activity in Rat Brain after Kainic Acid-Induced Status Epilepticus. Evid Based Complement Alternat Med. 2018;2018:7287820. https://doi.org/10.1155/2018/7287820
Obernier JA, Baldwin RL. Establishing an appropriate period of acclimatization following transportation of laboratory animals. ILAR J. 2006;47(4):364–369. https://doi.org/10.1093/ilar.47.4.364
Gage GJ, Kipke DR, Shain W. Whole animal perfusion fixation for rodents. J Vis Exp. 2012;(65):e3564. https://doi.org/10.3791/3564
Paxinos G, Watson C. The rat brain in stereotaxic coordinates: hard cover edition. Elsevier; 2006.
Feldman AT, Wolfe D. Tissue processing and hematoxylin and eosin staining. Methods Mol Biol. 2014;1180:31–43. https://doi.org/10.1007/978-1-4939-1050-2_3
Garman RH. Histology of the central nervous system. Toxicol Pathol. 2011;39(1):22–35. https://doi.org/10.1177/0192623310389621
Mahale A, Fikri F, Al Hati K, Al Shahwan S, Al Jadaan I, Al Katan H, Khandekar R, Maktabi A, Edward DP. Histopathologic and immunohistochemical features of capsular tissue around failed Ahmed glaucoma valves. PLoS One. 2017;12(11):e0187506. https://doi.org/10.1371/journal.pone.0187506
Mustafa HN, El Awdan SA, Hegazy GA, Abdel Jaleel GA. Prophylactic role of coenzyme Q10 and Cynara scolymus L on doxorubicin-induced toxicity in rats: Biochemical and immunohistochemical study. Indian J Pharmacol. 2015;47(6):649–656. https://doi.org/10.4103/0253-7613.169588
Mattson MP. Chapter 11 - Excitotoxicity. In: Fink G (Ed.). Stress: Physiology, Biochemistry, and Pathology. Academic Press; 2019:125–134. https://doi.org/10.1016/B978-0-12-813146-6.00011-4
Verma M, Lizama BN, Chu CT. Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration. Transl Neurodegener. 2022;11(1):3. https://doi.org/10.1186/s40035-021-00278-7
Löscher W, Stafstrom CE. Epilepsy and its neurobehavioral comorbidities: Insights gained from animal models. Epilepsia. 2023;64(1):54–91. https://doi.org/10.1111/epi.17433
Georgescu Margarint EL, Georgescu IA, Zahiu CDM, Tirlea SA, Şteopoaie AR, Zǎgrean L, Popa D, Zǎgrean AM. Reduced Interhemispheric Coherence in Cerebellar Kainic Acid-Induced Lateralized Dystonia. Front Neurol. 2020;11:580540. https://doi.org/10.3389/fneur.2020.580540
Nam HY, Na EJ, Lee E, Kwon Y, Kim H-J. Antiepileptic and Neuroprotective Effects of Oleamide in Rat Striatum on Kainate-Induced Behavioral Seizure and Excitotoxic Damage via Calpain Inhibition. Front Pharmacol. 2017;8:817. https://doi.org/10.3389/fphar.2017.00817
Pisa M, Sanberg PR, Fibiger HC. Locomotor activity, exploration and spatial alternation learning in rats with striatal injections of kainic acid. Physiol Behav. 1980;24(1):11–19. https://doi.org/10.1016/0031-9384(80)90007-4
Zhang P, Duan L, Ou Y, Ling Q, Cao L, Qian H, Zhang J, Wang J, Yuan X. The cerebellum and cognitive neural networks. Front Hum Neurosci. 2023;17:1197459. https://doi.org/10.3389/fnhum.2023.1197459
Streng ML, Krook-Magnuson E. The cerebellum and epilepsy. Epilepsy Behav. 2021;121:106909. https://doi.org/10.1016/j.yebeh.2020.106909
Lee M, Cheng MM, Lin C-Y, Louis ED, Faust PL, Kuo S-H. Decreased EAAT2 protein expression in the essential tremor cerebellar cortex. Acta Neuropathol Commun. 2014;2:157. https://doi.org/10.1186/s40478-014-0157-z
Rabenstein M, Peter F, Rolfs A, Frech MJ. Impact of Reduced Cerebellar EAAT Expression on Purkinje Cell Firing Pattern of NPC1-deficient Mice. Sci Rep. 2018;8(1):3318. https://doi.org/10.1038/s41598-018-21805-z
Yoo SY, Kim JH, Do SH, Zuo Z. Inhibition of the activity of excitatory amino acid transporter 4 expressed in xenopus oocytes after chronic exposure to ethanol. Alcohol Clin Exp Res. 2008;32(7):1292–1298. https://doi.org/10.1111/j.1530-0277.2008.00697.x
Perkins EM, Clarkson YL, Suminaite D, Lyndon AR, Tanaka K, Rothstein JD, Skehel PA, Wyllie DJA, Jackson M. Loss of cerebellar glutamate transporters EAAT4 and GLAST differentially affects the spontaneous firing pattern and survival of Purkinje cells. Hum Mol Genet. 2018;27(15):2614–2627. https://doi.org/10.1093/hmg/ddy169
Wadiche JI, Jahr CE. Patterned expression of Purkinje cell glutamate transporters controls synaptic plasticity. Nat Neurosci. 2005;8(10):1329–34. https://doi.org/10.1038/nn1539
Mancini A, Ghiglieri V, Parnetti L, Calabresi P, Di Filippo M. Neuro-Immune Cross-Talk in the Striatum: From Basal Ganglia Physiology to Circuit Dysfunction. Front Immunol. 2021;12:644294. https://doi.org/10.3389/fimmu.2021.644294
Brodovskaya A, Shiono S, Kapur J. Activation of the basal ganglia and indirect pathway neurons during frontal lobe seizures. Brain. 2021;144(7):2074–2091. https://doi.org/10.1093/brain/awab119
Planas-Fontánez TM, Dreyfus CF, Saitta KS. Reactive Astrocytes as Therapeutic Targets for Brain Degenerative Diseases: Roles Played by Metabotropic Glutamate Receptors. Neurochem Res. 2020;45(3):541–550. https://doi.org/10.1007/s11064-020-02968-6
Umpierre AD, West PJ, White JA, Wilcox KS. Conditional knock-out of mGluR5 from astrocytes during epilepsy development impairs high-frequency glutamate uptake. J Neurosci. 2019;39(4):727–742. https://doi.org/10.1523/JNEUROSCI.1148-18.2018
Obeid M, Frank J, Medina M, Finckbone V, Bliss R, Bista B, Majmudar S, Hurst D, Strahlendorf H, Strahlendorf J. Neuroprotective effects of leptin following kainic acid-induced status epilepticus. Epilepsy Behav. 2010;19(3):278–283. https://doi.org/10.1016/j.yebeh.2010.07.023
Drexel M, Preidt AP, Sperk G. Sequel of spontaneous seizures after kainic acid-induced status epilepticus and associated neuropathological changes in the subiculum and entorhinal cortex. Neuropharmacology. 2012;63(5):806–817. https://doi.org/10.1016/j.neuropharm.2012.06.009
Matias I, Morgado J, Gomes FCA. Astrocyte Heterogeneity: Impact to Brain Aging and Disease. Front Aging Neurosci. 2019;11:59. https://doi.org/10.3389/fnagi.2019.00059
Silva RFM, Pogačnik L. Polyphenols from food and natural products: Neuroprotection and safety. Antioxidants. 2020;9(1):61. https://doi.org/10.3390/antiox9010061
Grabska-Kobyłecka I, Szpakowski P, Król A, Książek-Winiarek D, Kobyłecki A, Głąbiński A, Nowak D. Polyphenols and Their Impact on the Prevention of Neurodegenerative Diseases and Development. Nutrients. 2023;15(15):3454. https://doi.org/10.3390/nu15153454
Tang SP, Wan Yusuf WN, Abd Aziz CB, Mustafa M, Mohamed M. Effects of six-month tualang honey supplementation on physiological and biochemical profiles in asymptomatic, treatment-naïve HIV-infected patients. Trop J Nat Prod Res. 2020;4(12):1116–1123.
Lin TY, Lu CW, Wang SJ. Luteolin protects the hippocampus against neuron impairments induced by kainic acid in rats. Neurotoxicology. 2016;55:48–57. https://doi.org/10.1016/j.neuro.2016.05.008
Maya S, Prakash T, Madhu K. Assessment of neuroprotective effects of Gallic acid against glutamate-induced neurotoxicity in primary rat cortex neuronal culture. Neurochem Int. 2018;121:50–58. https://doi.org/10.1016/j.neuint.2018.10.011