Behavioral Deficit and Decreased GABA Receptor Functional Regulation in the Hippocampus of Epileptic Rats: Effect of Bacopa monnieri

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, GABA, and GAD were down regulated (P < 0.001) in the hippocampus of the epileptic rats compared to control. GABA 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.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. 1.

    Mody I (2005) Aspects of the homeostaic plasticity of GABAA receptor-mediated inhibition. J Physiol 562:37–46

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    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

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    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

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    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

    CAS  PubMed  Google Scholar 

  5. 5.

    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

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    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

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    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

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Olton DS, Papas BC (1979) Spatial memory and hippocampal function. Neuropsychologia 17:669–682

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Rosane BB, Helena MT (2004) Carbamazepine enhances discriminative memory in rat model of epilepsy. Epilepsia 45:1443–1447

    Article  Google Scholar 

  10. 10.

    Kwan P, Brodie MJ (2001) Neuropsychological effects of epilepsy and antiepileptic drugs. Lancet 357:216–222

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Martin S, Jones M, Simpson E, Van den Buuse M (2003) Impaired spatial reference memory in aromatase-deficient (ArKO) mice. Neuroreport 14:1979–1982

    Google Scholar 

  12. 12.

    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

    Article  Google Scholar 

  13. 13.

    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

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Leung LS, Boon KA, Kaibara T, Innis NK (1990) Radial maze per-formance following hippocampal kindling. Behav Brain Res 40:119–129

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    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

  16. 16.

    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

    Article  Google Scholar 

  17. 17.

    Sing HK, Dhawan BN (1997) Neuropsychopharmacological effects of the Ayurvedic nootropic Bacopa monniera Linn. (Brahmi). Indian J Pharmacol 29:359–365

    Google Scholar 

  18. 18.

    Russo A, Borrelli F (2005) Bacopa monniera, a reputed nootropic plant: an overview. Phytomedicine 12:305–317

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    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

    Google Scholar 

  20. 20.

    Singh HK, Dhawan BN (1982) Effect of Bacopa monniera Linn. (brahmi) extract on avoidance responses in rat. J Ethnopharmacol 5:205–214

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    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

  22. 22.

    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

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Mathew J, Paul J, Nandhu MS, Paulose CS (2009) Bacopa monnieri and Bacoside–A for ameliorating epilepsy associated behavioral deficits. Fitoterapia. PMID: 19944749

  24. 24.

    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

    Article  Google Scholar 

  25. 25.

    Racine RJ (1972) Modification of seizure activity by electrical stimulation. After discharge threshold. Electroencephalogr Clin Neurophysiol 32:269–279

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Lowry OH, Roserbbrough N, Farr AL, Randall RJ (1951) Protein measurement with Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  27. 27.

    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

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Scatchard G (1949) The attractions of proteins for small molecules and ions. Ann NY Acad Sci 51:660–672

    CAS  Article  Google Scholar 

  29. 29.

    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

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    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

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    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

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    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

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    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

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    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

    Article  Google Scholar 

  35. 35.

    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

    Google Scholar 

  36. 36.

    Lavenex P, Amaral DG (2000) Hippocampal-neocortical interaction: a hierarchy of associativity. Hippocampus 10:420–430

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Squire LR, Stark CE, Clark RE (2004) The medial temporal lobe. Annu Rev Neurosci 27:279–306

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    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

    Article  Google Scholar 

  39. 39.

    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

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    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

    Google Scholar 

  41. 41.

    Quan L, Meili G, Chang BS, Lowenstein DH (2003) Epilepsy. N Engl J Med 349:1257–1266

    Article  Google Scholar 

  42. 42.

    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

    Article  Google Scholar 

  43. 43.

    Aggleton JP, Brown MW (1999) Episodic memory, amnesia, and the hippocampal–anterior thalamic axis. Behav Brain Sci 22:425–444

    CAS  PubMed  Google Scholar 

  44. 44.

    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

    Article  PubMed  Google Scholar 

  45. 45.

    Daniel A, Levy RO, Hopkins LR (2004) Squire Impaired odour recognition memory in patients with hippocampal lesions. Learn Mem 11:794–796

    Article  Google Scholar 

  46. 46.

    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

    Article  Google Scholar 

  47. 47.

    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

    CAS  PubMed  Google Scholar 

  48. 48.

    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

    Article  PubMed  Google Scholar 

  49. 49.

    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

    Article  Google Scholar 

  50. 50.

    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

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    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

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    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

    CAS  Google Scholar 

  53. 53.

    Chapman CA, Lacaille JC (1999) Intrinsic theta-frequency membrane potential oscillations in hippocampal CA1 interneurons of stratum lacunosum-moleculare. J Neurophysiol 81:1296–1307

    CAS  PubMed  Google Scholar 

  54. 54.

    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

    Article  PubMed  Google Scholar 

  55. 55.

    Murugesan T (2005) Evaluation of psychopharmacological effects of Linn. Extract Phytomedicine 8:472–476

    Article  Google Scholar 

  56. 56.

    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

    CAS  Article  Google Scholar 

  57. 57.

    Singh HK, Dhawan BN (1982) Effect of Bacopa monniera Linn. (brahmi) extract on avoidance responses in rat. J Ethnopharmacol 5:205–214

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Bhattacharya SK, Ghosal S (1998) Anxiolytic activity of a standardized extract of Bacopa monniera—an experimental study. Phytomedicine 5:77–82

    CAS  Google Scholar 

  59. 59.

    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

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    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

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    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

  62. 62.

    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

    CAS  PubMed  Google Scholar 

  63. 63.

    Dey PK, Datta C (1966) Effect of psychotropic phytochemicals on cerebral amino acid level. Indian J Exp Biol 4:216–218

    CAS  PubMed  Google Scholar 

  64. 64.

    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

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Russo A, Borrelli F, Campisi A (2003) Nitric oxide-related toxicity in cultured astrocytes: effect of Bacopa monnieri. Life Sci 73:1517–1526

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    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

    Article  Google Scholar 

  67. 67.

    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

    CAS  Article  PubMed  Google Scholar 

Download references

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to C. S. Paulose.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Keywords

  • Epilepsy
  • Bacopa monnieri
  • Bacoside-A
  • Pilocarpine
  • Carbamazepine