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Neurobiological Technologies, Inc. (Nasdaq: NTII) is focused on the development of drugs to protect nerve cells from injury and death. In a number of acute and chronic medical conditions, including neuropathic pain, stroke, traumatic brain injury, and dementia, overactivation of the N-methyl-D-aspartate (NMDA) receptors on the membranes of neurons leads to neuronal injury, resulting in serious neurological problems. Thus, drugs that modulate or inhibit the activity of NMDA receptors have the potential to provide neuroprotection (protect neurons and preserve neurologic function).
Neuronal injury contributes significantly to functional impairment in a wide variety of peripheral and central nervous system disorders. Such disorders include trauma to the brain from stroke or head injury; and chronic diseases such as diabetes, AIDS, Parkinson's and Alzheimer's. Neurologic impairments characteristic of these disorders include loss of coordination and inability to walk, memory loss, inability to concentrate and other cognitive deficits. Such impairments often become permanent and progressively worse over hours, days, weeks (in stroke and traumatic brain injury) and years (in chronic disorders). An effective neuroprotectant may be able to slow or halt this progression of functional impairment.
Current therapies do not adequately prevent or treat neuronal injury. Thus, an effective neuroprotectant drug could provide substantial new therapeutic benefit for many groups of patients.
Nerve cells communicate by sending signals that excite or inhibit each other via chemical messengers called neurotransmitters. These neurotransmitters bind to receptors embedded in the cell membranes of neurons. The most common excitatory neurotransmitter, glutamate, binds to the NMDA receptor. When activated by glutamate, the NMDA receptor opens a channel in the cell membrane through which electrically charged calcium atoms pass. Calcium flows into the cell, reversing the electrical charge of the neuron. This process stimulates the neuron to send signals to adjacent neurons. Normal functioning of the NMDA receptor is essential to thought, movement and perception.
Normally, neurotransmitter levels are highly regulated by the nervous system. In certain medical conditions, injured nerve cells become unable to control the normal release of neurotransmitters and "dump" excess glutamate into the extracellular environment. Excess glutamate results in overexcitation of the NMDA receptor allowing excess calcium to enter the affected neurons (see drawing). These neurons may then swell and rupture, releasing more glutamate into the surrounding area, which in turn overexcites NMDA receptors on adjacent neurons. This cascade of neuronal injury, referred to as "excitotoxicity," follows acute conditions such as stroke and traumatic brain injury. Nerve cells also appear to release excess glutamate in certain chronic conditions such as neuropathic pain and dementia.
Drug candidates that prevent excessive activation of the NMDA receptor, NMDA receptor antagonists, may have the ability to reduce the potentially damaging and lethal influx of calcium into neurons. There is presently considerable medical and commercial interest to develop NMDA receptor antagonists to treat neurodegenerative disorders. Many NMDA receptor antagonists previously evaluated in human clinical trials either prevented glutamate from binding to the NMDA receptor, or blocked the NMDA receptor channel for a longer period of time than was safe (see drawing). While they protected neurons from excitotoxicity, they also prevented normal signal communication and interfered with essential functioning. Such interference resulted in some cases in hallucinations, psychosis or even coma. The first NMDA receptor antagonist tested in humans, Merck's MK-801, produced neuropsychiatric side effects. A well-known NMDA receptor antagonist, phencyclidine, is also overly potent, producing undesireable effects as well. Certain other compounds tested in clinical trials have also shown serious side effects similar to those of MK-801.
Unlike many other NMDA receptor antagonists previously tested and now in development, Memantine acts to modulate the NMDA receptor calcium channel, rather than to block it completely. It stays in the channel long enough to reduce the calcium influx, but not so long that it blocks calcium flow completely, interfering with normal functioning (see drawing). The profound side effects associated with many other calcium channel blockers have not been reported with therapeutic doses of Memantine.
NTI is sponsoring research aimed at developing novel therapies for acute neuronal damage and chronic neuronal degeneration. Leading neuroscientists are participating in the program, including Stuart A. Lipton, M.D., Ph.D. of the Harvard Medical School Department of Neurology and Children's Hospital of Boston. Dr. Lipton has published seminal work in cellular and molecular neuroscience, and is a noted expert on the function of the NMDA receptor.
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