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NMDA Receptor Biology & Disease Relevance:
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Many neurological disorders are characterized by excessive or prolonged
activation of glutamate receptors, which ultimately damages or kills neurons.
The NMDA-responsive type of glutamate ionotropic receptors has been implicated
in epilepsy and neurological disorders including neuropathic pain, Alzheimer’s, Huntington’s, and Parkinson’s diseases.
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In epilepsy, competitive NMDA-receptor channel blockers can be effective in reducing seizures in some patients, but most available drugs and compounds have undesirable side effects that preclude clinical utility or dramatically effect quality of life and patient compliance.
Epilepsy represents an annual global market of over $5 billion. There are over two million epilepsy patients in the US alone, with an estimated 200,000
new patients diagnosed each year. One in four adults living with epilepsy
cannot control their seizures through current medications, and existing seizure medications provide therapeutic benefit to only 40% (approx.) of children who experience infantile seizures.
Neurodegenerative Diseases
There is increasing evidence that excessive activation of NMDA-receptors is
causally involved in catastrophic progressive neurodegenerative diseases such as
Alzheimer's disease, Huntington's disease, Parkinson's disease and ALS or
“Lou Gehrig’s Disease”. This hyper activation of NMDA-
receptors can occur as a consequence of the pathological expression of the
mutant protein complexes causing these diseases. Pharmacological agents that
attenuate NMDA-receptor function have been shown to reduce the damage and
effects of these pathological processes. As an example of the success of this
approach, memantine, a NMDA-receptor channel blocker, was recently approved by
the FDA for the treatment of Alzheimer's disease.
Neuropathic Pain
Neuropathic pain can result from lesions or damage to the nervous system. It is
often associated with diabetes, viral infections, multiple sclerosis, spinal
cord injury, and cancer or cancer therapy. Neuropathic pain is long lasting,
debilitating, and a major detriment to a patient’s quality of life.
Current drug treatment is relatively ineffective and has significant side
effects. The activation and regulation of NMDA-receptors is taking center stage
as a basic mechanism involved in neuropathic pain. Critical research and
development is focused on the hypersensitivity of damaged nerves and alterations
in the activation of secondary pain pathways. NMDA-receptor antagonists have
been reported to be effective in neuropathic pain animal models. Clinical trials
have shown that anticonvulsant, such as gabapentin and carbamazepine, have some efficacy in neuropathic pain but have significant side effects that
can reduce their therapeutic utility.
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