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Journal Article 2013; 34(6): 529-538 PubMed PMID: 24378454 Citation  Keywords:  Animals, Antibodies, Monoclonal:pharmacology, Apoptosis:drug effects, Boron Compounds:pharmacology, Cells, Cultured, Cerebellum:cytology, Cytokine Receptor gp130:antagonists & inhibitors, Dantrolene:pharmacology, Drug Interactions, Excitatory Amino Acid A.   

OBJECTIVE: To reveal the involvement of inositol 1,4,5-trisphosphate receptors (IP3R) and ryanodine receptors (RyR) in IL-6 prevention from neuronal apoptosis and necrosis induced by N-methyl-D-aspartate (NMDA).

METHODS: Cerebellar granule neurons (CGNs) from 8-day-old rats were exposed to IL-6 for 8 days and then stimulated with NMDA for 30 min. The 2-aminoethoxydiphenyl borate (2-APB) and dantrolene (DAN) were used to antagonize IP3R and RyR, respectively. Anti-gp130 monoclonal antibody (mAb) was employed to neutralize gp130, a 130-kDa signal-transducing β-subunit of IL-6 receptor complex. Neuronal apoptosis and necrosis were determined by TUNEL, fluorometric caspase-3 enzyme activity, annexin V-FITC/PI staining and ELISA. Western blot and real-time PCR measured IP3R1 and RyR2 expression, respectively.

RESULTS: IL-6 prevented the elevation of TUNEL-positive cells and caspase-3 expression and activity, and also suppressed the increase in annexin V-FITC/PI-positive cells and DNA- and histone-associated nucleosomes in cultured CGNs evoked by NMDA. These anti-apoptotic and anti-necrotic effects of IL-6 were larger on DAN-treated cells than on 2-APB-exposed neurons, since 2-APB treatment alone significantly inhibited the neuronal apoptosis and necrosis but DAN exposure alone did not alter the apoptosis and necrosis induced by NMDA. In support of these results, IL-6 downregulated IP3R1 but did not affect RyR2 expression. All these IL-6 effects were blocked by anti-gp130 mAb.

CONCLUSION: IL-6 prevention from NMDA-triggered Ca2+-induced Ca2+ release-mediated apoptosis and necrosis in CGNs depends on the inhibition of IP3R channel opening and expression rather than on RyR activity. IL-6 receptor-coupled gp130 signaling mediates this neuroprotection of IL-6 resistance to neuronal apoptosis and necrosis....

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Journal Article 2011; 32(6): 816-820 PubMed PMID: 22286796 Citation  Keywords:  Animals, Bungarotoxins:metabolism, Excitatory Amino Acid Agonists:pharmacology, Hippocampus:cytology, Kainic Acid:pharmacology, Neurons:cytology, Neuroprotective Agents:pharmacology, Nicotine:pharmacology, Nicotinic Agonists:pharmacology, Protein Isoforms.   

OBJECTIVES: Our previous study showed that administration of nicotine is capable to protect the neurons of hippocampus against the kainic acid induced damage. Here we tested the hypotheses that multiple nicotine administration would prevent the effects of kainic acid on neuronal nicotinic receptor subtypes densities (α-bungarotoxin sensitive and α-bungarotoxin insentive) and on hippocampal cell degeneration.

METHODS: Radioligand binding study was used to detect the particular nAChR subtypes densities. Two histochemical methods (bis-benzimide staining and Fluoro-Jade B dye) were used to detect and evaluate neuronal degeneration.

RESULTS: Our study shows that: a) kainic acid single administration increased the number of α-bungarotoxin insentive nicotinic receptors, b) nicotine was able to prevent such changes, c) repeated nicotine administration is capable to attenuate the damage of CA1 and CA3 areas of the hippocampus. No effect on α-bungarotoxin sentive nicotinic receptors was observed. Our data therefore reveal the importance of α-bungarotoxin insentive nicotinic receptors in the response to kainite and the ability of nicotine to prevent such changes both in the cell degeneration and in number of receptors.

CONCLUSION: Nicotine administration influences α-bungarotoxin insensitive receptors and repeated administration is capable to protect against toxicity caused by kainic acid in hippocampal area....

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Journal Article 2005; 26(3): 225-230 PubMed PMID: 15990726 Citation  Keywords:  Animals, Blood Glucose:drug effects, Cholinesterase Inhibitors:pharmacology, Denervation, Entorhinal Cortex:cytology, Excitatory Amino Acid Agonists, Hippocampus:cytology, Ibotenic Acid, Male, Microinjections, Neostigmine:pharmacology, Neural Pathways, Ra.   

OBJECTIVE: Microinjectin of neostigmine, an inhibitor of acetylcholine esterase, into the rat hippocampus elicited stress-like responses reflected by the release of adrenocorticotropic hormone (ACTH) and blood glucose elevations. The entorhinal cortex is regarded as an interface between the hippocampus and neocortex. The current study was designed to examine the role of the entorhinal cortex in regulation of blood glucose elevation induced by hippocampal neostigmine injection.

MATERIAL AND METHODS: We produced the entorhinal cortex lesions in 9 week-old male Wistar rats by the bilateral injections of the cell-selective neurotoxin, ibotenic acid (15microg/microl). Two weeks after the injections, neostigmine methylsulfate (sigma, 5x10(-8) mol) was microinjected into the rat hippocampus in a volume of 1microl for 1min using a CMA/100 microinjection pump. Plasma ACTH levels were measured by radioimmunoassay. Plasma glucose concentrations were determined by the immobilized enzyme membrane/H2O2 method with a compact glucose analyzer Antsense II (Bayer Medical Co.Ltd,Tokyo, Japan).

RESULTS: Compared with sham-operated control rats, the entorhinal lesions produced by ibotenic acid significantly attenuated the elevations of blood glucose evoked by the microinjection of neostigmine into the hippocampus. However, no significant difference of plasma ACTH in response to the injection was observed between the entorhinal-lesioned rats and controls.

CONCLUSION: The results of the present study indicate that the entorhinal cortex plays a role in the central nervous systems regulation of blood glucose and may be involved in a stress response presumably via an alternative pathway....

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Journal Article 2003; 24(6): 435-439 PubMed PMID: 15073571 Citation  Keywords:  2-Amino-5-phosphonovalerate:pharmacology, Age Factors, Animals, Dizocilpine Maleate:pharmacology, Excitatory Amino Acid Antagonists:pharmacology, Hypothalamus:drug effects, Injections, Intraventricular, Male, Prolactin:metabolism, Rats, Rats, Wistar, Rece.   

OBJECTIVE: To investigate the effects of N-methyl-D-aspartate (NMDA) receptor antagonists on restraint-induced release of prolactin (PRL) in male Wistar rats of different ages.

DESIGN: Rats were implanted with a brain ventricular for icv injection, and with a jugular vein cannula for iv injection. Competitive NMDA receptor antagonist AP-5 and noncompetitive NMDA receptor blocker MK-801 was injected via brain cannula or vein cannula and was restrained for 3 hours. The blood sample was collected through vein cannula during the restraint. The plasma concentration of prolactin was measured by RIA.

RESULTS: The restraint-induced PRL release in the adult rat (12-weeks) was significantly suppressed by MK-801 (50 microg/rat, icv; or 5 mg/kg, iv) and was partially inhibited by pretreatment of AP-5 (50, 100 microg/rat, icv), but was not changed by systemic administration of AP-5 (10 mg/kg, iv). MK-801 (5 mg/kg, iv) prevented the restraint-induced PRL release in the peripuberal rat (45-days) and in the middle-aged rat (16-months).

CONCLUSION: Central NMDA receptors mediate restraint-induced PRL release in the male rat....

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