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(Drug information on 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(Drug information on 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."
