Recent Biochemical Developments in Epilepsy: Case Study of Glutamate and GABA
Abstract
Epilepsy is a neurological disorder characterized by recurrent seizures that cause changes in attention or behaviour (Brodie et al., 2012). Epileptic seizures occur due to abnormal, excessive, and hyper-synchronous neuronal activity in the brain (Bromfield et al., 2006). Currently, antiepileptic drugs are ineffective for 30% of all epileptic patients and most only provide short-term relief and have high levels of inter-patient variability in treatment effectiveness (Pack, 2011; Seifert et al., 2010; Tatum, 2013). These treatments do not directly address the core causes of epilepsy, which include acquired damage to neural circuits, congenital abnormalities, and genetic deficiencies (Tatum, 2013). This is attributed to a lack of understanding of the molecular pathways responsible for epileptogenesis (Goldberg and Coulter, 2013). Because it affects approximately 50 million people worldwide, it is critical to understand the underlying biochemical mechanisms contributing to this condition to develop more effective therapeutics (Banerjee et al., 2009).
References
Banerjee, P.N., Filippi, D., and Allen Hauser, W. (2009). The descriptive epidemiology of epilepsy-a review. Epilepsy Res. 85, 31–45.
Brodie, M.J., Barry, S.J.E., Bamagous, G.A., Norrie, J.D., and Kwan, P. (2012). Patterns of treatment response in newly diagnosed epilepsy. Neurology 78, 1548–1554.
Bromfield, E.B., Cavazos, J.E., and Sirven, J.I. (2006). Basic Mechanisms Underlying Seizures and Epilepsy.
Chin, R.F. (2014). What are the best ways to deliver benzodiazepines in children/patients with prolonged convulsive seizures? Epileptic Disord. 16 Suppl 1, 50–58.
Ciociola, A.A., Cohen, L.B., and Kulkarni, P. (2014). How drugs are developed and approved by the FDA: current process and future directions. Am. J. Gastroenterol. 109, 620–623.
DiNuzzo, M., Mangia, S., Maraviglia, B., and Giove, F. (2014). Physiological bases of the K+ and the glutamate/GABA hypotheses of epilepsy. Epilepsy Res. 108, 995–1012.
Eid, T., Thomas, M.J., Spencer, D.D., Rundén-Pran, E., Lai, J.C.K., Malthankar, G. V, Kim, J.H., Danbolt, N.C., Ottersen, O.P., and de Lanerolle, N.C. (2004). Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy. Lancet 363, 28–37.
Fritsch, B., Reis, J., Gasior, M., Kaminski, R.M., and Rogawski, M.A. (2014). Role of GluK1 kainate receptors in seizures, epileptic discharges, and epileptogenesis. J. Neurosci. 34, 5765–5775.
Goldberg, E.M., and Coulter, D.A. (2013). Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction. Nat. Rev. Neurosci. 14, 337–349.
Gospe, S.M., Olin, K.L., and Keen, C.L. (1994). Reduced GABA synthesis in pyridoxine-dependent seizures. Lancet 343, 1133–1134.
Huberfeld, G., Menendez de la Prida, L., Pallud, J., Cohen, I., Le Van Quyen, M., Adam, C., Clemenceau, S., Baulac, M., and Miles, R. (2011). Glutamatergic pre-ictal discharges emerge at the transition to seizure in human epilepsy. Nat. Neurosci. 14, 627–634.
Jourdain, P., Bergersen, L.H., Bhaukaurally, K., Bezzi, P., Santello, M., Domercq, M., Matute, C., Tonello, F., Gundersen, V., and Volterra, A. (2007). Glutamate exocytosis from astrocytes controls synaptic strength. Nat. Neurosci. 10, 331–339.
Lagae, L. (2014). Overview of clinical efficacy and risk data of benzodiazepines for prolonged seizures. Epileptic Disord. 16 Suppl 1, 44–49.
Pack, A.M. (2011). Treatment of epilepsy to optimize bone health. Curr. Treat. Options Neurol. 13, 346–354.
Patsalos, P.N. (2013). Drug interactions with the newer antiepileptic drugs (AEDs)--part 1: pharmacokinetic and pharmacodynamic interactions between AEDs. Clin. Pharmacokinet. 52, 927–966.
Peeters, K., Adriaenssen, I., Wapenaar, R., Neto, W., and Pledger, G. (2003). A pooled analysis of adjunctive topiramate in refractory partial epilepsy. Acta Neurol. Scand. 108, 9–15.
Privitera, M.D. Generic antiepileptic drugs: current controversies and future directions. Epilepsy Curr. 8, 113–117.
Rundfeldt, C., and Löscher, W. (2014). The pharmacology of imepitoin: the first partial benzodiazepine receptor agonist developed for the treatment of epilepsy. CNS Drugs 28, 29–43.
Seifert, G., Carmignoto, G., and Steinhäuser, C. (2010). Astrocyte dysfunction in epilepsy. Brain Res. Rev. 63, 212–221.
Siegel, G.J., Agranoff, B.W., Albers, R.W., Fisher, S.K., and Uhler, M.D. (1999). Basic Neurochemistry.
Tatum, W.O. (2013). Recent and Emerging Anti-seizure Drugs: 2013. Curr. Treat. Options Neurol. 15, 505–518.
