Am I off the track in my excitement about the recent post on  GPI-1046?
This to me appears to be a MAJOR breakthrough !! If what they are reporting
in this article holds true for humans we may really get our "lives back"!!=
=20
Pill Stimulates CNS Neurons' Regrowth
by Kenneth J. Bender, Pharm.D.
April 1997

Orally active compounds called neuroimmunophilins were demonstrated to
protect and to stimulate the regeneration of brain cells in animal models
with Parkinson's disease, according to a study published in the March 4
issue of the Proceedings of the National Academy of Sciences.
The study was written by Joseph Steiner, Ph.D., and colleagues in the
neurobiological research and medicinal chemistry departments of Guilford
Pharmaceuticals, and communicated by Solomon Snyder, M.D., department of
neurosciences, Johns Hopkins University School of Medicine. These
researchers found that the experimental compound GPI-1046 exerted potent
neuroprotective effects for nigrostriatal dopamine neurons exposed to the
concurrently administered neurotoxin, MPTP
(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). When the neuroimmunophilin
was administered up to one month after an ablative course of either MPTP,
or another neurotoxin, 6-OHDA (6-hydroxydopamine), it promoted regenerative
sprouting in the few nigrostriatal neuronal fibers remaining intact
(Steiner and colleagues).
Snyder, who described the neuroimmunophilins and their potential at the
annual meeting of the American College of Neuropsychopharmacology (ACNP) in
December, related to Psychiatric Times that these compounds "represent the
first instance of agents that make damaged nerves grow back with restored
function."
Peter Suzdak, Ph.D., vice president of research at Guilford and a coauthor
of the Proceedings report, had previously commented on the investigation at
the November meeting of the Society for Neurosciences. "The results
obtained with GPI-1046 are to our knowledge unprecedented and the
first-ever demonstration of a nerve regenerative effect with an orally
active small molecule," he said.
"I know of nothing which has previously demonstrated both such a potent
regenerative effect on damaged brain neurons and a near normalization of
animal behavior as we have shown with GPI-1046."
The development of the novel neuroimmunophilin compounds was based on
observations that the "immunophilin" receptor proteins for
immunosuppressant drugs like cyclosporin A (Sandimmune) are 10- to 50-fold
more abundant in the nervous system than in immune tissue; and that
increased mRNA expression of an immunophilin (FKBP-12) following a neural
lesion occurs with enhancement of a protein (GAP-43) that has been
associated with neurite extension. Following the determination that
immunosuppressant drugs, affecting GAP-43, also enhance neurite extension,
researchers then developed a series of compounds as ligands of the FKBP-12
immunophilin receptor protein that exert potent neurotrophic activity
without suppressing the immune system.
Steiner commented on the activity of these compounds. "One of the most
striking features of the neurotrophic actions of these neuroimmunophilin
ligands is their efficacy and potency. GPI-1046 has produced significant
enhancement of neurite outgrowth in sensory ganglia at concentrations as
low as 1 picomolar. This means its neurotrophic potency is greater than
that of nerve growth factor itself."
Steiner and colleagues cited comparative data in the report which indicate
that GPI-1046 is more potent in regenerating striatal dopaminergic markers
after MPTP than epidermal growth factor, nerve growth factor, glial cell
line-derived neurotrophic factor, and gangliosides or their synthetic
derivatives.
Craig Hamilton, Ph.D., second author of the study, added, "Another
potential advantage of GPI-1046 is that it is orally active and crosses the
blood-brain barrier. Thus, it should not be limited by the drug delivery
problems associated with protein and peptide growth factors."
(Cerebroventricular infusions of nerve growth factor for Alzheimer's
disease were described in Psychiatric Times, August 1994, p5.)
An additional important distinction from many neurotrophic polypeptides is
that the immunophilin ligands do not appear to induce aberrant sprouting of
neuronal processes when administered to normal animals. Steiner and
colleagues wrote, "In normal rats and mice, we have carefully examined
sciatic and facial nerves as well as numerous areas of the brain and spinal
cord and failed to observe any suggestions of abnormal sprouting."
In this current report, the researchers described GPI-1046 stimulating
partial morphological recovery in animal sciatic nerve fibers following
crush injury, and in central serotonin neurons following
parachloroamphetamine (PCA)-induced lesions. In a model of Parkinson's
disease in mice, nigrostriatal neurons are destroyed by MPTP-induced
oxidative free radical mechanisms. The protective effects of GPI-1046 were
demonstrated in this model when concurrent administration of the
neuroimmunophilin and MPTP spared more than twice the number of striatal
dopamine neurons compared to controls exposed to MPTP/vehicle.
In a paradigm more closely fashioned to clinical remediation of a
preexisting disorder, the researchers then administered GPI-1046 well after
the maximal destruction of dopamine neurons by neurotoxins. The
regenerative properties of the compound were evidenced by two- to threefold
higher striatal innervation densities in treated animals than in the
MPTP/vehicle controls. A similar recovery was achieved after neuronal
destruction by 6-OHDA, with an approximate 30% restoration of striatal
dopamine compared to controls. The reinnervation stimulated by GPI-1046 was
described as "many clusters or small branches of processes emerging from
the sparse network of spared nigrostriatal fibers, suggestive of terminal
and collateral sprouting."
In addition to morphological and biochemical neuronal restoration, the
researchers reported achieving functional recovery in these neurotoxic
animals which, prior to receiving the neuroimmunophilin, had exhibited
functional deficit behavior in apomorphine or amphetamine-induced
rotational movements. This success, along with restoring approximately 30%
of striatal dopamine "fits," the researchers note "with abundant evidence
that only about a third of normal dopamine innervation is required for
physiologic motor activity."
The portent of these results and the potential of these new compounds were
enthusiastically described by Guilford CEO, Craig Smith, M.D. "Based on our
experiments to date," he said, "we are actively investigating our
neuroimmunophilin ligands as potential treatments for a range of
neurodegenerative disorders such as Parkinson's disease, Alzheimer's
disease, multiple sclerosis, traumatic head and spinal cord injuries,
stroke and peripheral neuropathies such as diabetic neuropathy."
References
1.      Snyder SH. Novel neural messengers: therapeutic implications.
Presented in symposium, From the
Bench to the Bed (Office) Side: New Directions for Preclinical Models of
Clinical Symptoms and Drug Development, at the 35th Annual Meeting of the
American College of Neuropsychopharmacology, San Juan, Dec. 9, 1996.
2.      Steiner JP, Hamilton GS, Ross DT, et al. Neurotrophic immunophilin
ligands stimulate structural and functional recovery in neurodegenerative
animal models. Proc Natl Acad Sci.
1997;94:2019-2024.




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POTENTIAL PARKINSON'S DISEASE
                                 CURE

   Drug repairs brain's nerve cells, banishes most disease
                      symptoms in animal trials

Washington, DC - Parkinson's Disease may be reversible if a drug that has
worked in animal tests is as successful in humans. Results with the
compound will be presented at the American Chemical Society national
meeting in San Francisco on April 15, and were recently published in a
scientific journal.* The  drug, developed by Guilford Pharmaceuticals of
Baltimore, represent a "tremendously exciting" advance, says Dr. Jonathan
Pincus, M.D., a Georgetown University physician who is a Parkinson's
disease expert. Pincus says this is "the first time there has been a
compound that could get into the brain and stimulate nerve growth."
Parkinson's patients, who include boxer Muhammad Ali, develop
tremors,muscle weakness and shuffling gait as the nerve cells (neurons) in
the brain involved in motor control are gradually destroyed. More that 1.5
million Americans suffer from
the disease, which ultimately renders patients entirely rigid. The drug
works by regenerating damaged neurons, resulting in more than 90 percent
recovery of normal behavior in animal trials, says Dr. Gregory Hamilton,
principal scientist in Guilford's research department. "What we're really
excited about is that these compounds don't just slow down progression of
the disease." The animal trials suggest "we may be able to take patients
who have begun to show the outward manifestations of Parkinson's disease -
the tremor, the motor-control deficits - and push them back over the
threshold into normal behavioral function. We hope to
reverse the disease and not simply slow it down." Hamilton believes this
reversibility is "completely unprecedented for an orally active small
molecule. There is nothing out there now that holds the promise of taking
people with these sorts of tragic diseases and pushing them back to some
degree of normal  function." So far the compound, along with a number of
similar analogs, has been successfully tested in rats and mice, without
turning up any problems with toxicity or side effects. They are now being
xamined in rhesus monkeys, and Hamilton says human clinical trials might
begin at the end of this year or early next
year. The compounds, which can be administered orally, are small molecules
termed neuroimmunophilin ligands. They bind ellular proteins known
asimmunophilins. Intriguingly, the animal tests show these compounds can
regenerate other
types of damaged nerves, without affecting normal, healthy neurons.
Hamilton says that means these drugs could potentially treat nerve damage
in conditions such as diabetes, carpal tunnel syndrome or Bell's palsy.
Further, the compounds "protect other types of neurons in the brain against
toxic damage," Hamilton says. So Guilford is looking into their impact on
Alzheimer's disease, with "encouraging initial results." Other potential
targets include multiple sclerosis, traumatic head and spinal cord injuries
and stroke. Hamilton adds that "it is our feeling at this point that almost
any disease that involves chronic degeneration of nerves may be affected in
a positive manner by these compounds. They appear to have an extremely
general effect to promote regeneration of damaged nerves." For more
information contact:                        American Chemical Society
                         Kirk Monroe, 202/872-4445

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 Disease
Cure

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