Abstract
In the present study, alterations of the General GABA and GABAA receptors in the hippocampus of pilocarpine-induced temporal lobe epileptic rats and the therapeutic application of Bacopa monnieri and its active component Bacoside-A were investigated. Bacopa monnieri (Linn.) is a herbaceous plant belonging to the family Scrophulariaceae. Hippocampus is the major region of the brain belonging to the limbic system and plays an important role in epileptogenesis, memory and learning. Scatchard analysis of [3H]GABA and [3H]bicuculline in the hippocampus of the epileptic rat showed significant decrease in Bmax (P < 0.001) compared to control. Real Time PCR amplification of GABAA receptor sub-units such as GABAAά1, GABAAά5, GABAAδ, and GAD were down regulated (P < 0.001) in the hippocampus of the epileptic rats compared to control. GABAAγ subunit was up regulated. Epileptic rats have deficit in the radial arm and Y maze performance. Bacopa monnieri and Bacoside-A treatment reverses all these changes near to control. Our results suggest that decreased GABA receptors in the hippocampus have an important role in epilepsy associated behavioral deficit, Bacopa monnieri and Bacoside-A have clinical significance in the management of epilepsy.
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Mody I (2005) Aspects of the homeostaic plasticity of GABAA receptor-mediated inhibition. J Physiol 562:37–46
Tsunashima K, Schwarzer C, Kirchmair E, Sieghart W, Sperk G (1997) GABA(A) receptor subunits in the rat hippocampus III: altered messenger RNA expression in kainic acid-induced epilepsy. Neuroscience 80:1019–1032
Brooks-Kayal AR, Shumate MD, Jin H, Rikhter TY, Coulter DA (1998) Selective changes in single cell GABA(A) receptor subunit expression and function in temporal lobe epilepsy. Nat Med 4:1166–1172
Loup F, Wieser HG, Yonekawa Y, Aguzzi A, Fritschy JM (2000) Selective alterations in GABAA receptor subtypes in human temporal lobe epilepsy. J Neurosci 20:5401–5419
Baulac S, Huberfeld G, Gourfinkel-An I, Mitropoulou G, Beranger A, Prud’homme JF, Baulac M, Brice A, Bruzzone R, LeGuern E (2001) First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene. Nat Genet 28:46–48
Wallace RH, Marini C, Petrou S, Harkin LA, Bowser DN, Panchal RG, Williams DA, Sutherland GR, Mulley JC, Scheffer IE, Berkovic SF (2001) Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet 28:49–52
Cossette P, Liu L, Brisebois K, Dong H, Lortie A, Vanasse M, Saint-Hilaire JM, Carmant L, Verner A, Lu WY, Wang YT, Rouleau GA (2002) Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet 31:184–189
Olton DS, Papas BC (1979) Spatial memory and hippocampal function. Neuropsychologia 17:669–682
Rosane BB, Helena MT (2004) Carbamazepine enhances discriminative memory in rat model of epilepsy. Epilepsia 45:1443–1447
Kwan P, Brodie MJ (2001) Neuropsychological effects of epilepsy and antiepileptic drugs. Lancet 357:216–222
Martin S, Jones M, Simpson E, Van den Buuse M (2003) Impaired spatial reference memory in aromatase-deficient (ArKO) mice. Neuroreport 14:1979–1982
Conrad CD, Grote KA, Hobbs RJ, Ferayorni A (2003) Sex differences in spatial and non-spatial Y-maze performance after chronic stress. Neurobio Learn Mem 79:32–40
Conrad CD, Lupien SJ, Thanasoulis LC, McEwen BS (1997) The effects of type I and type II corticosteroid receptor agonists on exploratory behavior and spatial memory in the Y-maze. Brain Res 759:76–83
Leung LS, Boon KA, Kaibara T, Innis NK (1990) Radial maze per-formance following hippocampal kindling. Behav Brain Res 40:119–129
Qing LI, Chun lJ, Li-sha XU, Zheng-bin ZG, Li-xia Y, Lu-ying L, Zhong C (2005) Histidine enhances carbamazepine action against seizures and improves spatial memory deficits induced by chronic transauricular kindling in rats. Acta Pharmacologica Sinica 26:1297–1302
Russo A, Izzo AA, Borrelli F, Renis M, Vanella A (2003) Free radical scavenging capacity and protective effect of Bacopa monniera L. on DNA damage. Phytother Res 17:46–54
Sing HK, Dhawan BN (1997) Neuropsychopharmacological effects of the Ayurvedic nootropic Bacopa monniera Linn. (Brahmi). Indian J Pharmacol 29:359–365
Russo A, Borrelli F (2005) Bacopa monniera, a reputed nootropic plant: an overview. Phytomedicine 12:305–317
Singh RH, Singh L (1980) Studies on the anti-anxiety effect of the medhya rasayana drug, Brahmi (Bacopa monniera Wettst.) -part 1. J Res Ayurveda Siddha 1:133–148
Singh HK, Dhawan BN (1982) Effect of Bacopa monniera Linn. (brahmi) extract on avoidance responses in rat. J Ethnopharmacol 5:205–214
Singh HK, Dhawan BN (1992) Drugs affecting learning and memory. In: Tandon PN, Bijiani V, Wadhwa S (eds) Lectures in neurobiology, vol 1. Wiley Eastern, New Delhi, pp 189–207
Deepak M, Amit A (2004) The need for establishing identities of ‘bacoside A and B’, the putative major bioactive saponins of Indian medicinal plant Bacopa monnieri. Phytomedicine 11:264–268
Mathew J, Paul J, Nandhu MS, Paulose CS (2009) Bacopa monnieri and Bacoside–A for ameliorating epilepsy associated behavioral deficits. Fitoterapia. PMID: 19944749
Paulose CS, Chathu F, Reas SK, Krishnakumar A (2008) Neuroprotective role of bacopa monnieri extract in epilepsy and effect of glucose supplementation during hypoxia: glutamate receptor gene expression. Neurochem Res 33:1573–6903
Racine RJ (1972) Modification of seizure activity by electrical stimulation. After discharge threshold. Electroencephalogr Clin Neurophysiol 32:269–279
Lowry OH, Roserbbrough N, Farr AL, Randall RJ (1951) Protein measurement with Folin phenol reagent. J Biol Chem 193:265–275
Kurioka S, Toshiaki K, Makoto M (1981) Effect of Sodim and Bicarbonate Ions on GABA Receptor binding in synaptic membrane of rat brain. J Neurochem 37:418–421
Scatchard G (1949) The attractions of proteins for small molecules and ions. Ann NY Acad Sci 51:660–672
Ma MX, Chen YM, He J, Zeng T, Wang JH (2007) Effects of morphine and its withdrawal on Y-maze spatial recognition memory in mice. Neuroscience 147:1059–1065
Akwa Y, Ladurelle N, Covey DF, Baulieu EE (2001) The synthetic enantiomer of pregnenolone sulfate is very active on memory in rats and mice, even more so than its physiological neurosteroid counterpart: distinct mechanisms? Proc Natl Acad Sci USA 98:14033–14037
Terra-Bustamante VC, Coimbra ÉR, Rezek KO, Escorsi-Rosset SR, Guarnieri R, Dalmagro CL, Inuzuka LM, Bianchin MM, Wichert-Ana L, Alexandre V, Takayanagui OM, Araújo D, dos Santos AC, Carlotti CG, Walz R, Markowitsch HJ, Sakamoto AC (2005) Cognitive performance of patients with mesial temporal lobe epilepsy and incidental calcified neurocysticercosis. J Neurol Neurosurg Psychiatry 76:1080–1083
Goffin K, Nissinen J, Van LK (2007) Cyclicity of spontaneous recurrent seizures in pilocarpine model of temporal lobe epilepsy in rat. Exp Neurol 205:501–505
Glien M, Brandt C, Potschka H, Loscher W (2002) Effects of the novel antiepileptic drug levetiracetam on spontaneous recurrent seizures in the rat pilocarpine model of temporal lobe epilepsy. Epilepsia 43:350–357
Hong J, Heng W, Gregory O, Jianning W, Kathleen D, Di S, Eric F, Che-Chang H, Richard D, Kopke Jang-Yen W (2003) Demonstration of functional coupling between γ-aminobutyric acid (GABA) synthesis and vesicular GABA transport into synaptic vesicles. Proc Natl Acad Sci USA 100:4293–4298
Joseph J, Niggemann B, Zaenker KS, Entschladen F (2002) The neurotransmitter γ-aminobutyric acid is an inhibitory regulator for the migration of SW 480 colon carcinoma cells. Cancer Res 22:6467–6469
Lavenex P, Amaral DG (2000) Hippocampal-neocortical interaction: a hierarchy of associativity. Hippocampus 10:420–430
Squire LR, Stark CE, Clark RE (2004) The medial temporal lobe. Annu Rev Neurosci 27:279–306
Schulz DW, Macdonald RL (1981) Barbiturate enhancement of GABA-mediated inhibition and activation of chloride ion conductance: correlation with anticonvulsant and anesthetic actions. Brain Res 23:177–188
MacDonald RL, Barker JL (1979) Enhancement of GABA-mediated postsynaptic inhibition in cultured mammalian spinal cord neurons: a common mode of anticonvulsant action. Brain Res 167:323–336
Ashok KS, Dennis AT (2000) Fetal hippocampal grafts containing CA3 cells restore host hippocampal glutamate decarboxylase-positive interneuron numbers in a rat model of temporal lobe epilepsy. J Neuroscience 20:8788–8801
Quan L, Meili G, Chang BS, Lowenstein DH (2003) Epilepsy. N Engl J Med 349:1257–1266
Gaffan D (1994) Scene-specific memory for objects: a model of episodic memory impairment in monkeys with fornix transection. J Cogn Neurosci 6:305–320
Aggleton JP, Brown MW (1999) Episodic memory, amnesia, and the hippocampal–anterior thalamic axis. Behav Brain Sci 22:425–444
Aggleton JP, McMackin D, Carpenter K, Hornak J, Kapur N, Halpin S (2000) Differential cognitive effects of colloid cysts in the third ventricle that spare or compromise the fornix. Brain 123:800–815
Daniel A, Levy RO, Hopkins LR (2004) Squire Impaired odour recognition memory in patients with hippocampal lesions. Learn Mem 11:794–796
Godehard W, Katrin B, Eva I (2004) Impaired associative memory in temporal lobe epilepsy subjects after lesions of hippocampus, parahippocampal gyrus, and amygdale. Hippocampus 14:785–796
Rausch R, Kraemer S, Pietras CJ, Le M, Vickrey BG, Passaro EA (2003) Early and late cognitive changes following temporal lobe surgery for epilepsy. Neurology 60:951–959
Blake RV, Wroe SJ, Breen EK, McCarthy RA (2000) Accelerated forgetting in patients with epilepsy Evidence for an impairment in memory consolidation. Brain 123:472–483
Butler CR, Zeman AZ (2008) Recent insights into the impairment of memory in epilepsy: transient epileptic amnesia, accelerated long-term forgetting and remote memory impairment. Brain 131:243–263
Stelzer A, Simon G, Kovacs G, Rai R (1994) Synaptic disinhibition during maintenance of long-term potentiation in the CA1 hippocampal subfield. Proc Natl Acad Sci USA 91:3058–3062
Lu YM, Mansuy IM, Kandel ER, Roder J (2000) Calcineurin-mediated LTD of GABAergic inhibition underlies the increased excitability of CA1 neurons associated with LTP. Neuron 26:197–205
Chapman CA, Lacaille JC (1999) Cholinergic induction of theta-frequency oscillations in hippocampal inhibitory interneurons and pacing of pyramidal cell firing. Neurosci 19:8637–8645
Chapman CA, Lacaille JC (1999) Intrinsic theta-frequency membrane potential oscillations in hippocampal CA1 interneurons of stratum lacunosum-moleculare. J Neurophysiol 81:1296–1307
Roodenrys S, Booth D, Bulzomi S, Phipps A, Micallef C, Smoker J (2002) Chronic effects of Brahmi (Bacopa monnieri) on human memory. Neuropsychopharmacology 27:279–281
Murugesan T (2005) Evaluation of psychopharmacological effects of Linn. Extract Phytomedicine 8:472–476
Singh HK, Rastogi RP, Srimal RC, Dhawan BN (1988) Effect of bacosides A and B on avoidance responses in rats. Phytother Res 2:70–75
Singh HK, Dhawan BN (1982) Effect of Bacopa monniera Linn. (brahmi) extract on avoidance responses in rat. J Ethnopharmacol 5:205–214
Bhattacharya SK, Ghosal S (1998) Anxiolytic activity of a standardized extract of Bacopa monniera—an experimental study. Phytomedicine 5:77–82
Sairam K, Dorababu M, Goel RK, Bhattacharya SK (2002) Antidepressant activity of standardized extract of Bacopa monniera in experimental models of depression in rats. Phytomedicine 9:207–211
Stough C, Lloyd J, Clarke J (2001) The chronic effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy human subjects. Psychopharmacology 156:481–484
Bhattacharya SK, Kumar A, Ghosal S (2000) Effect of Bacopa monniera on animal models of Alzheimer’s disease and perturbed central cholinergic markers of cognition in rats. In: Siva Sanka DV (eds), Molecular aspects of Asian medicine. PJD Publications, New York
Ganguly GK, Malhtora CL (1967) Some neuropharmacological and behavioral effects of an activefraction from Herpestis monniera Linn (Brahmi). Indian J Physiol Pharmacol 11:33–43
Dey PK, Datta C (1966) Effect of psychotropic phytochemicals on cerebral amino acid level. Indian J Exp Biol 4:216–218
Bhattacharya SK, Bhattacharya A, Kumar A, Ghosal S (2000) Antioxidant activity of Bacopa monniera in rat frontal cortex, striatum and hippocampus. Phytother Res 14:174–179
Russo A, Borrelli F, Campisi A (2003) Nitric oxide-related toxicity in cultured astrocytes: effect of Bacopa monnieri. Life Sci 73:1517–1526
Limpeanchob N, Jaipan S, Rattanakaruna S, Phrompittayarat W, Ingkaninan K (2008) Neuroprotective effect of Bacopa monnieri on beta-amyloid-induced cell death in primary cortical culture. J Ethnopharmacol 30:112–117
Chowdhuri DK, Parmar D, Kakkar P (2002) Antistress effects of bacosides of Bacopa monnieri: modulation of Hsp70 expression, superoxide dismutase and cytochrome P450 activity in rat brain. Phytother Res 16:639–645
Acknowledgments
This work was supported by research grants from DBT, DST, ICMR, Govt. of India and KSCSTE, Govt. of Kerala to Dr. C. S. Paulose. Jobin Mathew thanks CSIR for SRF.
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Mathew, J., Gangadharan, G., Kuruvilla, K.P. et al. Behavioral Deficit and Decreased GABA Receptor Functional Regulation in the Hippocampus of Epileptic Rats: Effect of Bacopa monnieri . Neurochem Res 36, 7–16 (2011). https://doi.org/10.1007/s11064-010-0253-9
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DOI: https://doi.org/10.1007/s11064-010-0253-9