We hypothesized that blockade of synthesis or release of several categories of neurotransmitters would ameliorate opioid neurotoxicity. Rats were randomly assigned to one of six groups in two sequential protocols: vesamicol (VES, n = 10), alpha-fluoromethylhistidine (FMH, n = 10), reserpine (RES, n = 10), BW1003C87 (BW, n = 7), lamotrigine (LAM, n = 10), or one of two control groups (CON, n = 19). Physiologically controlled rats received fentanyl (fen) i.v., loading dose 800 micrograms kg-1 followed by maintenance dose 32 micrograms kg-1 min-1 for 2 h. Drug dosing: CON, isovolemic (between rats) 0.9% saline i.v.; BW, 20 mg kg-1 i.v. 15 min pre-fen; LAM, 16 mg kg-1 i.v. 30 min pre-fen; VES, 2.5 mg kg-1 i.p. 60 min and 30 min pre-fen then infused 3.75 mg kg-1 during fen; FMH, 20 mg kg-1 i.p. 2 h pre-fen; RES, 0.75 mg kg-1 i.p. 18 h pre-fen. Seven days later all rats underwent cerebral perfusion fixation, followed by histologic grading (0-5, 0 = normal). Pathological data was analyzed by Wilcoxen's Signed rank test (two-tailed) for pathologic scores summated across all brain areas (overall severity score) and for scores of areas previously associated with opioid neurotoxicity. Compared to CON, overall severity was decreased by RES (p = 0.05) with an effect suggested by VES (p = 0.10). Compared to CON, lesions were decreased: (a) in the amygdala with VES (p = 0.03) and RES (p = 0.05) with a trend suggested by BW (p = 0.06); (b) in the subiculum by VES (p = 0.02) and RES (p = 0.008) with a trend suggested by FMH (p = 0.06); and (c) in the entorhinal cortex by VES (p = 0.004) and RES (p = 0.008) with a trend suggested by FMH (p = 0.07). The data indicate that brain acetylcholine and catecholamines contribute to opioid neurotoxicity, and suggest a possible role of glutamate and histamine in opioid neurotoxicity.

1999-12-01·Neuroscience Letters4区 · 医学

Effects of anticonvulsants on veratridine- and KCl-evoked glutamate release from rat cortical synaptosomes

4区 · 医学

Article

作者: Ratnakumari Lingamaneni ; Hugh C Hemmings

We compared the effects of three conventional (phenytoin, carbamazepine and phenobarbital) and three novel (BW 1003C87, lamotrigine and riluzole) anticonvulsants on evoked glutamate release from rat cortical synaptosomes. Glutamate release was evoked by either 20 microM veratridine (which requires both Na+ and Ca2+ channel activation) or 30 mM KCl (which requires Ca2+ channel, but not Na+ channel, activation) to assess the involvement of Na+ and/or Ca2+ channels in the presynaptic actions of these anticonvulsants. All six compounds inhibited veratridine-evoked glutamate release; BW 1003C87 (IC50 = 2.0 microM) was the most potent and phenobarbital (IC50 = 3.2 mM) was the least potent inhibitor. Only phenobarbital (IC50 = 6.4 mM), riluzole (IC50 > 50 microM) and phenytoin (IC50 > 800 microM) significantly inhibited KCl-evoked glutamate release. These results suggest that therapeutic concentrations of BW 1003C87, lamotrigine, phenytoin, carbamazepine and riluzole, but not phenobarbital, inhibit synaptic glutamate release by preferentially blocking presynaptic Na+ channels. Presynaptic Na+ channel blockade with inhibition of the release of glutamate, and possibly other transmitters, may contribute to their anticonvulsant and/or neuroprotective effects.

1999-12-01·European Journal of Neuroscience3区 · 医学

Nitric oxide stimulates cGMP formation in rat optic nerve axons, providing a specific marker of axon viability

3区 · 医学

Article

作者: John Garthwaite ; Giti Garthwaite ; David A. Goodwin

AbstractA major transduction pathway for nitric oxide (NO) is stimulation of soluble guanylyl cyclase and the generation of cyclic GMP (cGMP). In the central nervous system, the NO–cGMP pathway has previously been associated primarily with synapses, particularly glutamatergic synapses. We report here that NO caused a large increase in the levels of cGMP in a central white matter tract devoid of synapses, namely in the rat isolated optic nerve. Cyclic GMP immunohistochemistry indicated that this response was confined to the axons. Accordingly, nerves previously subjected to 1 h of oxygen/glucose deprivation, which leads to irreversible axonal damage, displayed an 80% reduction in their subsequent capacity to generate cGMP in response to NO and a corresponding reduction in the numbers of cGMP‐immunostained axons. Protection of the axon cGMP response against this insult was achieved by omission of Ca2 + or Na + from the incubation medium, and by the pharmacological agents tetrodotoxin, lamotrigine, BW619C89 and BW1003C87, all of which protect axonal structure from oxygen/glucose deprivation‐induced damage. The results suggest that the NO–cGMP pathway has a hitherto unsuspected function in the optic nerve. Additionally, the expression of NO‐stimulated guanylyl cyclase in optic nerve axons provides a simple, sensitive and specific marker of their functional integrity that is likely to be valuable in investigating the mechanisms responsible for axon degeneration in ischaemia and other conditions.

100 项与 BW-1003C87 相关的药物交易

登录后查看更多信息