NEW ORLEANS, Oct. 30, 1997
Today, scientists from Guilford Pharmaceuticals Inc. (Nasdaq:GLFD) presented animal data at the annual meeting of the Society for Neuroscience that suggest NAALADase (N-Acetylated- Alpha-Linked-Acidic-Dipeptidase) inhibition with a prototype compound, GPI- 5000, may represent a new target for treating stroke. This novel approach represents a fundamental departure from prior research efforts in the area of treating stroke.
For the first time, data is being presented this week relating to compounds which act by inhibiting NAALADase to regulate the production and release of glutamate, a novel mechanism of action discovered by Guilford. These data support that NAALADase inhibition may potentially be useful for the treatment of a range of neurodegenerative disorders believed to be caused by the toxicity of excess glutamate.
Based on the animal data presented today, Guilford believes that NAALADase inhibition may represent a completely new mechanism for regulating glutamate that is not only potentially effective in treating stroke, but may also be effective in the many other disorders involving excess glutamate including amyotrophic lateral sclerosis (ALS), epilepsy, head trauma, spinal cord trauma, peripheral neuropathies, and Parkinson's Disease.
``Guilford has discovered a novel, pre-synaptic approach to treating stroke which may have a significant impact on treatment for a range of devastating, neurodegenerative diseases,'' according to Dr. Peter Suzdak, Vice President of Research at Guilford. ``The animal data from these experiments demonstrates that by inhibiting NAALADase, we may be able to prevent excessive levels of glutamate from being produced and released, thereby protecting the cells from further damage after an ischemic event.''
Stroke
Stroke is a cerebrovascular injury that occurs when blood flow to the brain is
interrupted. This interruption deprives the brain of blood and oxygen which causes brain
cells to die. The brain cells destroyed within the initial injury of stroke set off a
chain reaction that also kills cells in the larger surrounding area. When brain cells die,
function of the body parts they control is impaired and lost causing paralysis, speech
problems, memory and reasoning deficits, coma and possibly death. Stroke is the third
leading cause of death in the United States, according to the National Stroke Association.
The Role of Glutamate
Glutamate is the major excitatory neurotransmitter found in the brain. Under normal
conditions, glutamate is released into the synapse and stimulates post-synaptic glutamate
receptors, specifically NMDA and AMPA. This stimulation plays a critical role in several
key functions in the brain including learning, memory and motor control. However, under
conditions of acute or chronic neurodegeneration such as stroke there is a large increase
in pre-synaptic glutamate release, which results in excessive stimulation of the
receptors, which leads to cell toxicity and cell death. As a result, glutamate has been
implicated in a large number of neurological disorders, including stroke, amyotrophic
lateral sclerosis (ALS), epilepsy, head trauma, spinal cord trauma, peripheral
neuropathies, and Parkinson's Disease.
Because of the large number of potential therapeutic applications, blocking excess glutamate has been an intense area of research throughout the pharmaceutical industry. However, to date, most of the activity has focused on compounds which would block glutamate from binding to the receptors after it has been produced and released, to try and prevent glutamate from damaging adjacent neurons. However, this approach has generally proven to be problematic, as clinical trials with such compounds have shown disappointing efficacy and potentially significant adverse side effects.
NAALADase
The data presented today focus on a novel means of blocking excessive glutamate before it
is produced and released. This mechanism is mediated by inhibition of the enzyme
NAALADase. In the brain during stroke and other ischemic events, a small peptide called
NAAG (N-Acetyl-Aspartyl-Glutamate) is converted by NAALADase into glutamate. As
demonstrated by the data presented today, inhibiting or restraining this process blocks
the production and release of excess glutamate.
``NAALADase inhibition is one key element in our multi-pronged neuroprotective research program,'' said Dr. Craig R. Smith, President and CEO of Guilford. ``We believe that our experimental results with NAALADase inhibition show real promise for a new upstream therapeutic target for stroke as well as other neurodegenerative conditions that may allow us to intervene and reduce the damage caused by these disorders. We will continue to focus significant effort on researching the effect of our proprietary compounds on this, and other neuroprotective mechanisms, in a variety of neurological diseases.''
Earlier this month, Guilford announced the issuance of its first U.S. patent relating to the composition of matter and use of NAALADase inhibitors. A total of 17 posters are being presented this week at the Society highlighting the innovative neurological research being conducted by Guilford. In addition to NAALADase research, posters are also being presented on two other key neurological research areas at Guilford: Poly(ADP-ribose) Synthetase (PARS), now called Poly (ADP-ribose) Polymerase (PARP), inhibition; and, FKBP- neuroimmunophilin ligands. According to the data presented this week, the inhibition of PARP with a prototype compound, GPI-6000, leads to a significant decrease in the infarction size in a focal cerebral ischemia model of stroke in the rat. This suggests that the activation of PARP may play an important role in the development of brain damage in cerebral ischemia through intracellular energy depletion.
Regarding Guilford's FKBP-neuroimmunophilin ligands, orally active small molecule neurotrophic agents, seven posters were presented yesterday on animal data that further confirms the potential regenerative and neurotrophic effects of one of the compounds in several devastating neurodegenerative diseases, including Parkinson's Disease, sciatic nerve injury and Alzheimer's Disease. Last month, Guilford announced results with GPI-1046 in a primate animal model of Parkinson's Disease, which is believed to be the first demonstration of a positive effect in this model with an orally active small molecule that promotes nerve growth and repair. On August 20, 1997, Guilford Pharmaceuticals and Amgen Inc. (Nasdaq:AMGN) entered into an agreement granting Amgen worldwide rights to develop, manufacture and sell Guilford's proprietary FKBP-neuroimmunophilin ligands.
Guilford Pharmaceuticals Inc. is a biopharmaceutical company engaged in the development of polymer-based drug delivery products for brain and other cancers, and novel products for the diagnosis and treatment of neurological diseases, including stroke, Parkinson's disease, Alzheimer's disease, head trauma, spinal cord injuries, multiple sclerosis, peripheral neuropathies and cocaine addiction.
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