Therapeutic potential of positive AMPA receptor modulators in the treatment of neurological disease

Abstract

Excitatory neurotransmission in the CNS depends heavily upon α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-type glutamate receptors. Derangements in AMPA receptor mediated synaptic transmission may be a contributing factor in neurological and neurodegenerative diseases and could be a target for therapeutic intervention. Recently, drugs that positively modulate AMPA receptors have been identified, having differential effects upon certain AMPA receptor subunits and different effects upon physiological properties of AMPA receptors. These drugs facilitate AMPA receptor mediated processes and may have beneficial therapeutic effects. For example, certain AMPA modulators facilitate long-term potentiation, which is considered a cellular mechanism that may be important for memory storage and they also facilitate memory encoding in behavioural experiments. Thus, AMPA modulators might ameliorate memory deficits that occur in dementia, such as Alzheimer’s disease (AD). However, AMPA receptor mediated excitotoxicity may occur with excessive AMPA receptor activation which occurs in seizures or ischaemia and positive AMPA modulators could promote neuronal injury in those conditions. Ultimately, the clinical utility of positive AMPA modulators will be dependent upon understanding the role of AMPA receptors in certain neurological disorders, identifying receptor subtypes involved in specific neurological disorders and developing drugs with selective actions upon specific AMPA receptor properties that also possess receptor subtype specificity. Currently available drugs have provided significant insight into the physiology and structural determinants of important AMPA receptor properties and some insight into potential clinical uses as well as potential dangers of such drugs.