Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used medicines worldwide and a common source of self-poisoning. These agents rapidly enter the Central Nervous System (CNS) and recent work has shown that they can delay the onset and slow the progression of Alzheimer's Disease. Several NSAIDs are also analgesic even when administered directly into the CNS and fenamate NSAIDs have anti-epileptic and neuroprotective properties. Despite these findings, little is known of the effects of these drugs on neuronal function. Recent experiments by the applicant have begun to address the hypothesis that NSAIDs modulate neuronal receptors and ion channels. Our initial experiments have concentrated on the effects of fenamate NSAIDs on GABA-A receptors. We have demonstrated that mefenamic acid modulates GABA-A receptors in the low therapeutic dose range and that such actions are highly receptor subtype selective. These data are important since they are the first to indicate that NSAIDs may have effects on synaptic transmission and suggest that such actions might contribute significantly to their clinical effects. These results also suggest that fenamates represent a new class of GABA-A receptor modulator with new but unrecognized therapeutic uses.
The aims of this study are, therefore, to address the hypothesis that NSAIDs have effects on neuronal function. This project will focus on the interaction between fenamate NSAIDs and central neuronal ligand- and voltage-gated ion channels. We will utilize single cell electrophysiological and cell culture techniques, firstly, to determine the molecular mechanism of action of fenamates on hippocampal neuron GABA-A receptors. Secondly we will further characterize the complex actions of fenamates on recombinant human GABA-A receptors. Thirdly, we will determine the selectivity of action of fenamates on neuronal function by determining their effects on several other native ligand- and voltage-gated ion channels. These experiments will contribute to our understanding of the molecular mechanisms by which NSAIDs produce their diverse central effects. These data may also provide new drug leads and/or novel molecular targets for the treatment of pain and/or neurodegenerative diseases such as Alzheimer's type dementias.
|Coyne, Leanne; Su, Jiping; Patten, Debra et al. (2007) Characterization of the interaction between fenamates and hippocampal neuron GABA(A) receptors. Neurochem Int 51:440-6|