Chlormethiazole hydrochloride

The protective action of chlormethiazole against ischaemia-induced neurodegeneration in gerbils when infused at doses having little sedative or anticonvulsant activity.[Pubmed:7599932]

Br J Pharmacol. 1995 Apr;114(8):1625-30.

1. The effect of chlormethiazole administration on delayed neuronal death in gerbil hippocampus following transient global ischaemia has been examined. Chlormethiazole was administered either intraperitoneally or by intravenous infusion with either the dose or the time of infusion varied. 2. Chlormethiazole (600 mumol kg-1, i.p.) given 60 min after ischaemia produced substantial (> 60%) neuroprotection when damage was assessed 5, 14 or 21 days later, indicating the drug does not merely delay cell death. 3. Infusion protocols were developed which would result in sustained and defined plasma concentrations. Chlormethiazole (930 mumol kg-1) was then infused intravenously for 30 min, 76.5 min or 110 min in ways resulting in sustained plasma concentrations of 200, 100 and 50 nmol ml-1 respectively. When treatment was initiated 30 min after the ischaemic episode all protocols provided effective neuroprotection. There was a dose-dependent decline in protection when plasma chlormethiazole concentrations of 50, 30 and 10 nmol ml-1 were sustained for 110 min with no protection observed at 10 nmol ml-1. 4. In contrast, when a plasma concentration of 10 nmol ml-1 was sustained by infusion for 24 h, almost total neuroprotection against the ischaemic damage was achieved. This plasma concentration produced no sedative or anticonvulsant activity. 5. These data suggest that neuroprotection depends on both dose and duration of chlormethiazole administration and that excellent neuroprotection is possible in the absence of the sedative and anticonvulsant effects of the drug.

Chlormethiazole, dizocilpine and haloperidol prevent the degeneration of serotonergic nerve terminals induced by administration of MDMA ('Ecstasy') to rats.[Pubmed:7539115]

Neuropharmacology. 1994 Dec;33(12):1589-95.

An investigation has been made into the effect of 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy') administration on the concentration of 5-hydroxytryptamine (5-HT), uptake of [3H]5-HT and [3H]paroxetine binding in rat cerebral cortex tissue. Four days after 2 injections of MDMA (20 mg/kg i.p., 6 hr apart) the concentrations of 5-HT and its metabolite 5-HIAA were reduced by 60%. The binding of [3H]paroxetine to the presynaptic 5-HT transporter was decreased and high affinity uptake of [3H]5-HT was reduced by a similar amount, indicating neurodegeneration of 5-HT terminals. Pretreatment with chlormethiazole (100 mg/kg i.p.), 10 min before each MDMA injection prevented the decrease in both [3H]parotextine binding and uptake of [3H]5-HT. The loss in 5-HT and 5-HIAA content was also attenuated. Pretreatment with dizocilpine (1 mg/kg i.p.) or haloperidol (2 mg/kg i.p.) also prevented the MDMA-induced loss of [3H]paroxetine binding and attenuated the loss of 5-HT and 5-HIAA content. All three compounds also decreased the degree of hyperthermia that follows MDMA administration, although previous studies suggest that the long term neurodegeneration is not associated with the acute hyperthermic response. These data support the findings of others that MDMA injection produces degeneration of 5-HT nerve terminals in the cortex, confirm that chlormethiazole, dizocilpine and haloperidol attenuate MDMA-induced neurotoxic loss of 5-HT and demonstrate for the first time that these compounds prevent the neurodegeneration of 5-HT nerve terminals that follows MDMA administration.