AMPA receptors in epilepsy and as targets for antiepileptic drugs.
نویسندگان
چکیده
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are key mediators of seizure spread in the nervous system and represent promising targets for antiepileptic drugs. There is emerging evidence that AMPA receptors may play a role in epileptogenesis and in seizure-induced brain damage. This evidence suggests that AMPA receptor antagonists could have broad utility in epilepsy therapy. Regional, developmental, and disease-associated variations in AMPA receptors produced by differential expression of AMPA receptor subunits and variations in posttranscriptional processing, including alternative splicing and pre-mRNA editing, provide a diversity of functionally distinct AMPA receptor isoforms that allow opportunities for selective drug targeting. Four types of AMPA receptor antagonist are discussed in this chapter: (a) competitive AMPA recognition site antagonists, including those of the quinoxalinedione and newer nonquinoxalinedione classes, (b) 2,3-benzodiazepine noncompetitive (allosteric) antagonists, (c) desensitization enhancing antagonists, exemplified by SCN-, and (d) antagonists of Ca(2+)-permeable AMPA receptors, including polyamine amide arthropod toxins and their synthetic analogues. Competitive and noncompetitive AMPA receptor antagonists are broad-spectrum anticonvulsants in animal seizure models. Their effectiveness and safety for humans remain to be determined. There is evidence that these antagonists can potentiate the antiseizure activity of N-methyl-D-aspartate (NMDA) receptor antagonists and conventional antiepileptic drugs. This evidence suggests that the preferred use of AMPA receptor antagonists may be in combination therapies. Agents that enhance desensitization may have advantages in comparison with other AMPA receptor antagonists to the extent that they preferentially block high-frequency synaptic signaling and avoid depressing AMPA receptors on interneurons, which would lead to disinhibition and enhanced excitability. Evidence has accumulated that Ca(2+)-permeable AMPA receptors (those lacking the edited GluR2 subunit) may play a role in epileptogenesis and the brain damage occurring with prolonged seizures. Because Ca(2+)-permeable AMPA receptors are predominately expressed in gamma-aminobutyric acid (GABA)ergic interneurons, it is hypothesized that some forms of epilepsy might be caused by reduced GABA inhibition resulting from Ca(2+)-permeable AMPA receptor-mediated excitotoxic death of interneurons. It is further proposed that drugs that selectively target Ca(2+)-permeable AMPA receptors might have antiepileptogenic and neuroprotective properties. Certain polyamine toxins and their analogues are channel-blocking AMPA receptor antagonists that selectively inhibit Ca(2+)-permeable AMPA receptors. These substances might give clues to the development of such antagonists.
منابع مشابه
Revisiting AMPA receptors as an antiepileptic drug target.
In the 1990s there was intense interest in ionotropic glutamate receptors as therapeutic targets for diverse neurological disorders, including epilepsy. NMDA receptors were thought to play a key role in the generation of seizures, leading to clinical studies of NMDA receptor blocking drugs in epilepsy. Disappointing results dampened enthusiasm for ionotropic glutamate receptors as a therapeutic...
متن کاملNewest Targets for Anticonvulsant Agents: An Overview
Epilepsy is a neurological condition characterized by recurrent seizures influencing about 1% of the worldwide population. Despite much progress in understanding the pathogenesis of epilepsy, the molecular basis of human epilepsy still remains unclear. Common approaches for pharmacotherapy of epilepsy are still directed towards controlling the symptoms and suppression of seizures. Clinical use ...
متن کاملEffect of IEM 1460 – a selective antagonist of GluR2-lacking AMPA receptors – on the action of conventional antiepileptic drugs against maximal electroshock in mice
The objective of the study was to determine the effect of combined treatment with IEM-1460 (a selective GluR2lacking, Ca2+ permeable AMPA receptors) and conventional antiepileptic drugs: CBZ (carbamazepine), valproate (VPA), phenobarbital (PB), and phenytoin (PHT) against maximal electroshock-induced convulsions in mice. IEM1460 (up to 30 mg/kg) did not show anticonvulsant action in the test fo...
متن کاملStructural Bases of Noncompetitive Inhibition of AMPA-Subtype Ionotropic Glutamate Receptors by Antiepileptic Drugs
Excitatory neurotransmission plays a key role in epileptogenesis. Correspondingly, AMPA-subtype ionotropic glutamate receptors, which mediate the majority of excitatory neurotransmission and contribute to seizure generation and spread, have emerged as promising targets for epilepsy therapy. The most potent and well-tolerated AMPA receptor inhibitors act via a noncompetitive mechanism, but many ...
متن کاملVOLTAGE-GATED ION CHANNELS Voltage-Gated Sodium Channels
Antiepileptic drugs (AEDs) protect against seizures through interactions with a variety of cellular targets. By affecting the functional activity of these targets, AEDs suppress abnormal hypersynchronous activity in brain circuits, leading to protection against seizures. The actions on these targets can be categorized into four broad groups: (i) modulation of voltage-gated ion channels, includi...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Advances in neurology
دوره 79 شماره
صفحات -
تاریخ انتشار 1999