strychnine and Huntington-Disease

During the past decade, converging lines of evidence have linked the abnormal release or leak of excitatory amino acids to the neurodegeneration associated with a wide range of pathologies including cerebral ischemias, Huntington's disease, and AIDS dementia (Coyle and Robinson, 1987; Lipton, 1994; Meldrum, 1994). Pharmacological studies indicate that activation of both ionotropic and metabotropic glutamate receptors can substantially contribute to excitotoxic cell damage (Choi, 1992; Pizzi et al., 1993; Sheardown et al., 1993; Xue et al., 1994). Based on these findings, therapeutic strategies based on blunting or blocking glutamatergic transmission may be useful in treating a variety of neurodegenerative disorders.

Topics: AIDS Dementia Complex; Amino Acids; Amino Acids, Cyclic; Animals; Brain Ischemia; Humans; Huntington Disease; Nerve Degeneration; Neurons; Neuroprotective Agents; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Strychnine

From binding studies using 3H-GABA and 3H-strychnine in dissected human brain material, inhibitory amino acid neurotransmitter receptors have a widespread distribution in the human CNS. Generally GABA receptors are predominant in the forebrain and upper brainstem whereas glycine receptors are more localized in the lower brainstem and spinal cord. Some areas (eg. the substantia nigra) have appreciable quantities of both receptors. Although glycine receptors are altered in some pathological conditions (eg. in Parkinson's disease, in the substantia nigra) the neuropharmacology of the glycine system is still poorly understood. On the other hand the GABA system has been intensively studied. Dysfunction of GABA receptors occurs in various neurological states, as epilepsy, Parkinson's disease and Huntington's chorea. Furthermore GABA agonists are active in animal models for dyskinesia, epilepsy and depression, amongst others. Clinical studies with progabide confirm these findings in animal models, and suggest that low-medium affinity GABA agonists are more appropriate clinical agents than are high or very high affinity GABA agonists. From these and many other findings there appears to be a very large potential for creating new pharmacological agents for different neuropsychiatric disorders based on agonist activity at inhibitory amino-acid receptors. From the example of progabide these compounds can be made not only specific for the receptor involved, but also to have a lower incidence of neurotoxic effects than presently available drugs.

Topics: Central Nervous System; Epilepsy; Humans; Huntington Disease; Mental Disorders; Nervous System Diseases; Neurotransmitter Agents; Parkinson Disease; Receptors, Cell Surface; Receptors, GABA-A; Receptors, Glycine; Seizures; Strychnine

Topics: Brain; Humans; Huntington Disease; Kinetics; Membranes; Parkinson Disease; Receptors, Cell Surface; Receptors, Glycine; Species Specificity; Spinal Cord; Strychnine

Specific [3H]strychnine binding was used to identify the glycine receptor macromolecular complex in human spinal cord, substantia nigra, inferior olivary nucleus, and cerebral cortex. In material from control patients a high-affinity KD (3--8 nM) was observed in the spinal cord and the substantia nigra, both the pars compacta and the pars reticulata. This is very similar to the values observed in the rat and bovine spinal cord (8 and 3 nM, respectively) and rat substantia nigra (12 nM). In the human brain the distribution of [3H]strychnine binding (at 10 nM) was: spinal cord = substantia nigra, pars compacta greater than substantia nigra, pars reticulata = inferior olivary nucleus greater than cerebral cortex. The binding capacity (Bmax) of the rat brain (substantia nigra or spinal cord) was approximately 10-fold that of the human brain. [3H]Strychnine binding was significantly decreased in the substantia nigra from Parkinson's disease patients, both in the pars compacta (67% of control) and the pars reticulata (50% of control), but not in the inferior olivary nucleus. The results were reproduced in preliminary experiment in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. In the substantia nigra from patients who died with Huntington's disease, [3H]strychnine binding tended to be high (150% of control, NS) in both the pars compacta and the reticulata. [3H]Strychnine binding was unaltered in the substantia nigra of patients with senile dementia. Together with previous neurophysiological and neuropharmacological findings, those results support the hypothesis of glycine receptors occurring on dopamine cell bodies and/or dendrites in the substantia nigra.

Topics: Adult; Aged; Animals; Brain; Cattle; Dementia; Female; Humans; Huntington Disease; Male; Middle Aged; Organ Specificity; Parkinson Disease; Rats; Receptors, Cell Surface; Receptors, Glycine; Species Specificity; Spinal Cord; Strychnine; Substantia Nigra; Tritium