cyclic-gmp and 3-acetylpyridine

The neuroprotective effects of pramipexole, a dopamine agonist, were investigated in 3-acetylpyridine (3-AP)-treated Wistar rats. Bromocriptine was used as a reference compound to compare the results obtained with pramipexole. A significant reduction (P < 0.01) in cerebellar cGMP and ATP was observed 96 h after treatment with 3-AP (500 micromol/kg, i.p.). Both pramipexole and bromocriptine significantly attenuated 3-AP-induced reduction in cerebellar cGMP and ATP. Consistent with the neurochemical effect, both pramipexole and bromocriptine prevented 3-AP-induced loss of motor coordination. 3-Acetylpyridine produced a significant (P < 0.01) loss of neurons in the inferior olivary nucleus. Treatment with pramipexole and bromocriptine partially, but significantly (P < 0.01), prevented the loss of inferior olivary neurons. There was no reduction in the temperature of the animals, indicating that hypothermia was not responsible for neuroprotection.

Topics: Adenosine Triphosphate; Animals; Benzothiazoles; Body Temperature; Bromocriptine; Cerebellum; Cyclic GMP; Dopamine Agonists; Male; Motor Activity; Neurons; Neuroprotective Agents; Neurotoxins; Olivary Nucleus; Pramipexole; Pyridines; Rats; Rats, Wistar; Thiazoles

The neuroprotective effects of U-101017, [7-chloro-5-[cis-3,5-dimethylpiperazine)carbonyl]-imidazole[1,5a]quinoli ne-3-carboxylate], a GABA(A) receptor partial agonist, were investigated in 3-acetylpyridine (3-AP) treated Wistar rats. A significant (P < 0.01) reduction in both cGMP and ATP in the cerebellum was observed at 96 h after treatment with 3-AP (500 micromol/kg i.p.). Oral administration of U-101017 before and after treatment with 3-AP significantly attenuated 3-AP-induced decreases in cGMP and ATP, and this effect was dose related. Consistent with the neurochemical effect, U-101017 prevented 3-AP-induced loss of motor coordination. Treatment with U-101017 partially, but significantly (P < 0.01) prevented the loss of inferior olivary neurons. U-101017 had no significant effect on body temperature. Thus, hypothermia was not involved in neuroprotective effects of U-101017. Co-administration of flumazenil with each treatment of U-101017 blocked the neuroprotective effect of U-101017, indicating that it mediated neuroprotection via the benzodiazepine binding sites on the GABA(A) receptor complex. Delayed administration of U-101017 at various time intervals after treatment with 3-AP demonstrated a significant neuroprotective effect even at 8 h, suggesting that this drug has a wide therapeutic window.

Topics: Adenosine Triphosphate; Animals; Body Temperature; Cerebellum; Cyclic GMP; Dose-Response Relationship, Drug; Flumazenil; GABA Modulators; GABA-A Receptor Agonists; Male; Movement; Neuroprotective Agents; Olivary Nucleus; Pyridines; Quinolines; Rats; Rats, Wistar; Time Factors

The neuroprotective effects of U-104067F[(9-(2-morpholinyl)ethyl) 2,4-di-l-pyrrolidinyl-9H-pyrimidino (4,5-b)(4,5indole monohydrochloride hydrate], a pyrrolopyrimidine antioxidant, were investigated in 3-acetylpyridine (3-AP)-treated Wistar rats. A significant (P < 0.01) reduction in cerebellar cGMP and ATP was observed at 96 h after treatment with 3-AP (500 micromol/kg ip). Oral administration of U-104067F significantly attenuated 3-AP-induced reductions in cGMP and ATP, and this effect was dose related. Consistent with the neurochemical effect, U-104067F prevented 3-AP-induced loss of motor coordination. 3-Acetylpyridine produced a significant (P < 0.01) loss of neurons in the inferior olivary nucleus. Treatment with U-104067F partially, but significantly (P < 0.01), prevented the loss of inferior olivary neurons. The physiological and neurochemical parameters were maintained within normal limits by U-104067F in 3-AP-treated rats despite only partial preservation of inferior olivary neurons.

Topics: Adenosine Triphosphate; Animals; Cell Count; Cyclic GMP; Dose-Response Relationship, Drug; Male; Neuroprotective Agents; Pyridines; Pyrimidines; Pyrrolidines; Rats; Rats, Wistar

Conjunctive stimulation of climbing and parallel fibres in the cerebellum evokes a long-term depression of parallel-fibre Purkinje-cell transmission, a phenomenon implicated as the cellular mechanism for cerebellar motor learning. It is suspected that the increase in cyclic GMP concentration that occurs after activation of climbing fibres is required to evoke long-term depression. Excitatory amino acids are known to cause the release of nitric oxide (NO), resulting in elevation of the cGMP level in the cerebellum. Here we report that endogenous NO is released after stimulation of climbing fibres, that long-term depression evoked by conjunctive stimulation of parallel and climbing fibres is blocked by haemoglobin (which strongly binds NO) or L-NG-monomethyl-arginine (an inhibitor of NO synthase), and that exogenous NO or cGMP can substitute for the stimulation of climbing fibres to cause long-term depression in rat cerebellar slices. These results demonstrate that the release of endogenous NO is essential for the induction of synaptic plasticity in the cerebellum.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Amino Acid Oxidoreductases; Animals; Arginine; Cerebellum; Cyclic GMP; Electric Stimulation; Electrophysiology; Excitatory Amino Acid Antagonists; Glutamic Acid; Hemoglobins; Male; Nitric Oxide; Nitric Oxide Synthase; omega-N-Methylarginine; Potassium; Purkinje Cells; Pyridines; Quinoxalines; Rats; Rats, Inbred Strains; Synapses

The inferior olivary nuclei (ION) of Sprague-Dawley rats were chemically lesioned with 3-acetylpyridine (3-AP), and the completeness verified by the lack of retrograde labeling of the ION following the injection of horseradish peroxidase (HRP) into the cerebellum. The effects of locomotor activity or of immobilization on cerebellar cyclic guanosine monophosphate (cGMP) levels were determined in control saline-treated and experimental, 3-AP-treated rats. Three subgroups of rats from both the control and the experimental groups of rats were required to swim for 60 s, immobilized for 60 s or unmanipulated before being killed by microwave irradiation, and the cerebella were collected for cGMP determination. There was no statistically significant difference in cGMP levels between immobilized and unmanipulated rats in either the experimental or control groups. Pretreatment with 3-AP reduced cerebellar cGMP levels in both the immobilized and the unmanipulated rats to 50% of those observed in the comparably treated groups of saline-treated controls. When compared to the corresponding group of unmanipulated rats, locomotor activity induced a significantly greater elevation of cerebellar cGMP in the experimental animals than in the controls (P less than 0.05). These results indicate that while inputs from the ION to the cerebellar Purkinje cells are probably important in maintaining the normal levels of cGMP seen in inactive rats, the locomotor-induced elevation of this parameter occurs in the absence of climbing fibers (from ION). The mechanisms responsible for the greater activity-induced elevation of cGMP levels seen in rats receiving 3-AP over control rats are discussed.

Topics: Animals; Cerebellum; Cyclic GMP; Female; Motor Activity; Neural Pathways; Olivary Nucleus; Pyridines; Rats; Rats, Inbred Strains; Swimming

The effects of a lesion of the inferior olive (the source of climbing fibres) has been investigated on a number of parameters of cerebellar excitatory amino acid function. Protoveratrine elicits a large increase in guanosine cyclic 3',5'-monophosphate levels in cerebellar slices, probably through the release of excitatory amino acids such as glutamate or aspartate, since the receptors involved are susceptible to specific antagonists. While the direct stimulatory (postsynaptic) effects of glutamate and related amino acids were not altered after loss of climbing fibres induced by 3-acetylpyridine, the guanosine cyclic 3',5'-monophosphate response to protoveratrine was markedly (40%) attenuated. Concomitant with this was a similar reduction in the high-affinity uptake of D-[3H]aspartate, a proposed marker for glutamate/aspartate terminals. Experiments to investigate the calcium-dependent, potassium-stimulated release of glutamate and aspartate, failed to reveal any reduction following acetylpyridine lesions. Although this latter finding does not exclude the possibility that these amino acids could be the transmitter of the climbing fibres, our data would rather suggest the involvement of some glutamate-like, but as yet unidentified, neuroexcitatory substance.

Topics: Afferent Pathways; Animals; Aspartic Acid; Brain Mapping; Cyclic GMP; Female; Glutamates; Glutamic Acid; Nerve Fibers; Olivary Nucleus; Purkinje Cells; Pyridines; Rats; Rats, Inbred Strains; Synaptic Transmission; Synaptosomes

The latencies and incidence of deltamethrin-induced motor symptoms were compared in rats pretreated with saline or 3-acetylpyridine (3-AP) (75 mg/kg i.p. 4 days before). 3-AP produced considerable degeneration of the inferior olive and hence the climbing fiber afferents to the cerebellar cortex. The times of onset of whole body tremor and spontaneous choreiform episodes were accelerated significantly in lesioned rats. Therefore the olivocerebellar tract is not important in mediating deltamethrin symptoms, but is necessary to compensate for the disruption of motor activity and coordination induced by deltamethrin at another site. Cerebellar cyclic guanosine monophosphate (cyclic GMP) levels were elevated significantly during the deltamethrin syndrome. The increase in cyclic GMP levels correlated directly with the duration of motor symptoms. This suggests that deltamethrin has an indirect effect on cerebellar cyclic GMP levels. Lesion of the olive-cerebellar tract did not abolish this rise in cerebellar cyclic GMP levels. The sequential development of the motor symptoms, whole body tremor followed by choreiform episodes was found to have an additive effect in raising cerebellar cyclic GMP levels. This suggests that both the nature and the general level of motor activity can influence cerebellar cyclic GMP levels.

Topics: Animals; Cerebellum; Cyclic GMP; Dyskinesia, Drug-Induced; Harmaline; Male; Motor Activity; Neural Pathways; Nitriles; Olivary Nucleus; Pyrethrins; Pyridines; Rats

Harmaline (28 mumoles/kg u.v.), cold exposure (4C) or isoniazid (2.2 mmoles/kg s.c.) increased the cGMP content in rat cerebellar cortex several fold. Isoniazid but not harmaline or cold exposure increased cGMP in the deep cerebellar nuclei (nuclei interpositus, vestibularis and fastigius) and striatum. In rats treated with the nicotinamide antagonist 3-acetylpyridine (3-AP) (0.66 mumoles/kg i.p. 4 days before) the tremorogenic effect of harmaline and the increase of cerebellar cortex cGMP produced by this alkaloid was abated. Similarly the increase of cGMP following exposure to cold was reduced. In contrast isoniazid and glutamate (10 mumoles intraventricularly) increased cGMP to the same extent in control and 3-AP treated rats. Since 3-AP produces in rat a massive degeneration of the inferior olivary nucleus and of the climbing fibers but leaves intact all the other cerebellar elements, these experiments suggest that an increase of cGMP content in postsynaptic cerebellar elements (presumable Purkinje cells) may be an expression of an increased release of an excitatory transmitter from either the climbing fivers or the parallel fibers.

Topics: Animals; Brain; Cerebellar Cortex; Cerebellar Nuclei; Cold Temperature; Cyclic GMP; gamma-Aminobutyric Acid; Harmaline; Isoniazid; Male; Purkinje Cells; Pyridines; Rats; Stress, Physiological

Topics: Alkaloids; Animals; Brain Chemistry; Cerebellar Cortex; Cyclic GMP; Glutamates; Harmaline; Male; Oxotremorine; Pyridines; Rats; Tremor