Gamma-amimo-butyric acid (GABA) is the major inhibitory neurotransmitter in human cortex and plays a pivotal role in suppressing the origin and spread of seizure activity. Nuclear magnetic resonance spectroscopy (NMRS) permits serial, non-invasive metabolite and macromolecule measurements without discomfort or known hazard for most people. Low CSF and tissue GABA concentrations in patients with epilepsy are associated with frequent seizures. Whether low GABA levels are the cause or the result of frequent seizures is unknown. The effectiveness of the class of antiepileptic drugs which target GABA metabolism , e.g., vigabitrin, gabapentin, tiagabine, depend on the elevation of GABA concentration. The focus of this proposal is the regulation of GABA and homocarnasine concentrations in patients with epilepsy.
Three aims propose to examine prospectively changes in occipital lobe GABA and homocarnazine induced by vigabatrin, gabapentin, and tiagabine. The purpose is to improve AED selection by developing guidelines based on GABA and homocarnosine levels. These NMRS measurements may provide a rational approach in selecting an appropriate drug. This proposal is the first attempt to provide estimates of """"""""therapeutic levels"""""""" for brain GABA and homocarnosine, similar to serum AED levels in widespread clinical use.
The fourth aim proposes to examine prospectively whether temporal lobectomy alters occipital lobe GABA and homocarnosine concentrations. The answer may impact both patient selection and the long-term post-surgical management. In the past decade, magnetic resonance methods have become standard of care in the evaluation of human epilepsy. NMRS based measurements of neurotransmitters and modulators should enter the clinical armamentarium in the next decade. This proposal will advance clinical care of seizure disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS032518-04A2
Application #
2605995
Study Section
Neurology A Study Section (NEUA)
Program Officer
Jacobs, Margaret
Project Start
1994-04-15
Project End
2001-03-31
Budget Start
1998-05-01
Budget End
1999-03-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Petroff, Ognen A C; Hyder, Fahmeed; Rothman, Douglas L et al. (2006) Brain homocarnosine and seizure control of patients taking gabapentin or topiramate. Epilepsia 47:495-8
Errante, Laura D; Petroff, Ognen A C (2003) Acute effects of gabapentin and pregabalin on rat forebrain cellular GABA, glutamate, and glutamine concentrations. Seizure 12:300-6
Petroff, Ognen A C (2002) GABA and glutamate in the human brain. Neuroscientist 8:562-73
Petroff, O A; Hyder, F; Rothman, D L et al. (2001) Homocarnosine and seizure control in juvenile myoclonic epilepsy and complex partial seizures. Neurology 56:709-15
Petroff, O A; Hyder, F; Rothman, D L et al. (2001) Topiramate rapidly raises brain GABA in epilepsy patients. Epilepsia 42:543-8
Petroff, O A; Hyder, F; Rothman, D L et al. (2000) Effects of gabapentin on brain GABA, homocarnosine, and pyrrolidinone in epilepsy patients. Epilepsia 41:675-80
Petroff, O A; Mattson, R H; Rothman, D L (2000) Proton MRS: GABA and glutamate. Adv Neurol 83:261-71
Petroff, O A; Hyder, F; Collins, T et al. (1999) Acute effects of vigabatrin on brain GABA and homocarnosine in patients with complex partial seizures. Epilepsia 40:958-64
Petroff, O A; Behar, K L; Rothman, D L (1999) New NMR measurements in epilepsy. Measuring brain GABA in patients with complex partial seizures. Adv Neurol 79:939-45
Petroff, O A; Rothman, D L; Behar, K L et al. (1999) Effects of valproate and other antiepileptic drugs on brain glutamate, glutamine, and GABA in patients with refractory complex partial seizures. Seizure 8:120-7

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