Eunyong Chung

Systemic 1-methyl, 4-phenyl, 1-2-3-6-tetrahydropyridine (MPTP) administration decreases retinal dopamine content in primates

Following MPTP administration, 4 Cynomolgus monkeys developed a parkinsonian syndrome, accompanied by specific changes of both pattern visual evoked potential and electroretinogram. Retinal dopamine and dihydroxyphenylacetic acid contents were measured in the 4 MPTP-treated monkeys and in 3 normal monkeys. Dopamine and dihydroxyphenylacetic acid levels were significantly lower in the retinas of the MPTP-treated animals (p less than 0.001), suggesting that dopamine has a specific function in the visual system of primates.

Acetyl-levo-carnitine protects against MPTP-induced parkinsonism in primates

SummaryAcetyl-levo-carnitine (ALC) protects against 1-methyl, 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity in the nonhuman primate. ALC pretreated monkeys do not show signs of parkinsonism or electroretinographic changes typical of dopaminergic deficiency when given MPTP. In addition, pilot neurochemical and morphological data confirm a partial protection effect. While MAO-B inhibitors, like L-Deprenyl, are thought to protect dopaminergic neurons from MPTP-induced cell death by preventing the conversion of MPTP to its toxic metabolite MPP+, ALC is not known to have MAO-B affnity. Converging evidence suggests that ALC may affect directly mitochondrial respiration, which is known to be the target of MPP+ and affected in human neurodegenerative diseases, including Parkinsons disease. The results of this study point to new therapeutic avenues for the treatment of these nosologic entities.

DDT myoclonus: Sites and mechanism of action

Intragastric injection of the insecticide DDT produces a stimulus-sensitive myoclonus in mice and rats. Unilateral stereotaxic infusions of DDT into rat medullary reticular formation also induced generalized myoclonus, identical to that produced by systemic administration. Similar myoclonus, but of lesser intensity, occurred when DDT was injected into cerebellar nuclei, red nucleus, and the inferior olive. Multiple other regions of the brain were resistant to the myoclonic action of locally infused DDT. Direct infusions into the medullary reticular formation of allethrin, which has a similar action on neuronal membranes as DDT, or the glycine receptor antagonist, strychnine, also elicited myoclonus.

Age-dependent changes in brain glycine concentration and strychnine-induced seizures in the rat.

Glycine levels and receptor binding were measured in the medulla and spinal cord of 2-month, 10-month, and 24-month-old Fischer 344 rats. The behavioral response to the administration of the glycine antagonist, strychnine, was also evaluated in 2- and 24-month-old animals to investigate the relevance of these parameters to the susceptibility to seizures. Significant reductions in glycine in both the spinal cord and medulla occurred from 2 to 24 months of age. The glycine precursors, serine and threonine, were decreased only in the spinal cord. [3H]Strychnine binding was also decreased by 38% and 34% in the medulla and spinal cord, respectively, of 24-month-old rats compared to 2-month-olds. [3H]GABA binding was similarly reduced while no age-related changes in [3H]diazepam binding in the spinal cord were detected. Comparison of 2- and 24-month-old animals after systemic injection of 1.75 mg/kg strychnine showed that senescent animals have a higher incidence of seizures and mortality compared to young animals. Decreases in glycinergic neurotransmission may lower strychnine seizure threshold in the aged animal.

Platelet monoamine oxidase in Parkinson patients: effect of L-deprenyl therapy

SummaryPlatelet MAO activity was measured in 79 Parkinson patients (56 males and 23 females) before and during L-deprenyl therapy. Baseline platelet MAO activity was higher in females than in males with no age dependent differences. During chronic L-deprenyl therapy, MAO activity was inhibited greater than 98%. Four hours after the oral administration of the first 5 mg dose of L-deprenyl, platelet MAO activity was inhibited by 86%. By 24 hours, greater than 98%, inhibition was achieved and this degree of inhibition was maintained during continuous L-deprenyl administration. Following oral administration of 10 mg L-deprenyl once a day versus 5 mg L-deprenyl twice a day, the time course of platelet MAO inhibition was similar. Five days after the termination of chronic L-deprenyl therapy, platelet MAO activity was still inhibited by 96%. MAO activity returned to normal by 2 weeks after stopping L-deprenyl. Platelet MAO activity is a useful method of monitoring bioavailability, compliance, dose-response relationship and optimal dosage schedules for L-deprenyl in Parkinson patients.

Urea-induced myoclonus: Medullary glycine antagonism as mechanism of action

Stimulus sensitive myoclonus is a prominent symptom of uremia in both man and animals. Intravenous injection of urea into cats had been previously reported to produce spike and sharp wave electrical discharges in the medullary reticular formation which correlated with the myoclonic movements. In the present investigations, intraperitoneal injections of 2 g/kg urea every 15 minutes for 4 injections produced myoclonus in rats accompanied by brain urea concentrations of 6.8 X 10(-2)M, which is sevenfold higher than normal. 10(-2) and 10(-1) M urea significantly reduced 3H-strychnine binding to rat medulla membranes by 30% and 43% respectively. Urea inhibition of 3H-strychnine binding was reversible and binding kinetics revealed that 10(-1)M urea decreased Bmax by 65% with no effect on the affinity. Brain glycine levels did not change after urea injections and urea had no effect on synaptosomal uptake of 3H-glycine. Urea did not alter 3H-GABA, 3H-glutamate and 3H-QNB receptor binding but decreased 3H-diazepam receptor binding in the medulla. Mannitol also reduced 3H-diazepam binding but had no effect on 3H-strychnine binding. Stereotaxic injection of the glycine receptor antagonist, strychnine, into the rat medullary reticular formation produced myoclonus, whereas Ro 15-1788, a benzodiazepine antagonist, had no effect. Urea may produce myoclonus by blockade of glycine receptors in the medullary reticular formation.

Characterization of dopamine receptors on neurons grown in primary dissociated cell culture from ventral mesencephalon of mouse.

Mammalian neurons from ventral mesencephalon were grown in primary dissociated cell culture. These cultures were examined for dopamine sensitive adenylate cyclase activity and specific ligand binding of [3H]spiroperidol and [3H]flupenthixol. No stimulation of adenylate cyclase activity by 10 microM dopamine was demonstrable in cell culture homogenates. [3H]Spiroperidol bound to cell culture homogenates with high affinity and was displaced by (+)-butaclamol but not by 5-hydroxytryptamine, suggesting that the [3H]spiroperidol was bound to dopamine receptors. While [3H]flupenthixol binding was also present, it could be displaced by spiroperidol indicating that the dopamine receptor was probably of the D2 subtype. Binding of spiroperidol was proportional to the amount of cell culture homogenate, and was saturable. Are these receptors autoreceptors? The toxin 1-methyl-4-phenylpyridine (MPP+) was used to destroy dopaminergic neurons; spiroperidol binding in these cultures was found to be increased, demonstrating that most of these D2 receptors are not autoreceptors.

Effect of inferior olive lesion on seizure threshold in the rat

Cerebellar stimulation has been associated with anticonvulsant activity in several experimental seizure models. We examined the effect of destruction of cerebellar climbing fibers, by systemic administration of 3-acetylpyridine (3AP) or electrothermic lesion of the inferior olive, on seizures produced by various chemical convulsants in rats. We found that inferior olive lesioned rats had lower threshold to seizures induced by strychnine and brucine, both glycine antagonists. The dose response curve for strychnine seizure was shifted 2.5 times to the left in 3AP lesioned rats. No difference in seizure threshold was seen when picrotoxin, bicuculline or pentylenetetrazole PTZ) were used to produce seizures. Abnormal motor behavior (AMB) including myoclonus, backward movement and hyperextension, produced by all of the convulsants tested, was significantly aggravated in 3AP pretreated rats. The inferior olive-climbing fiber projection to the cerebellum appears to modulate seizures induced by inhibition of glycinergic neurotransmission.

The effects of inferior olive lesion on strychnine seizure

Bilateral inferior olive lesions, produced by systemic administration of the neurotoxin 3-acetylpyridine (3AP) produce a proconvulsant state specific for strychnine-induced seizures and myoclonus. We have proposed that these phenomena are mediated through increased excitation of cerebellar Purkinje cells, through activation of glutamate receptors, in response to climbing fiber deafferentation. An increase in quisqualic acid (QA)-displaceable [3H]AMPA [(RS)-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid] binding in cerebella from inferior olive-lesioned rats was observed, but no difference in [3H]AMPA binding displaced by glutamate, kainic acid (KA) or glutamate diethylester (GDEE) was seen. The excitatory amino acid antagonists GDEE and MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10 imine] were tested as anticonvulsants for strychnine-induced seizures in 3AP inferior olive-lesioned and control rats. Neither drug effected seizures in control rats, however, both GDEE and MK-801 produced a leftward shift in the strychnine-seizure dose-response curve in 3AP inferior olive-lesioned rats. GDEE also inhibited strychnine-induced myoclonus in the lesioned group, while MK-801 had no effect on myoclonus. The decreased threshold for strychnine-induced seizures and myoclonus in the 3AP-inferior olive-lesioned rats may be due to an increase in glutamate receptors as suggested by the [3H]AMPA binding data.

Strychnine seizure potentiation by azaspirodecanedione anxiolytics in rats

Buspirone, gepirone and ipsaperone administered intraperitoneally (40 mg/kg) to naive rats were found to be proconvulsive for strychnine-induced seizures. The dose of strychnine required to induce seizures in 50% of test animals (CD50) was 2.18 mg/kg in naive rats, while CD50s for rats treated with the azaspirodecanediones ipsaperone, gepirone and buspirone were 1.65, 0.97 and 0.70 mg/kg respectively. Azaspirodecanediones have high affinity for the 5-HT1A serotonin receptor, however, the specific 5-HT1A agonist, 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT) had no effect on strychnine seizure in naive rats (CD50 = 2.0 mg/kg). The strychnine specific proconvulsive effects of inferior olive lesions and buspirone were additive, resulting in a CD50 of 0.1 mg/kg. This observation indicates that the buspirone-induced decrease in strychnine seizure threshold does not require intact inferior olive-climbing fiber pathways. Cerebellar sites for possible azaspirodecanedione action are discussed.