The effects of 8-OH-DPAT on neuroinflammation after sarin exposure in mice.
ABSTRACT Poisoning by organophosphate nerve agents can induce seizures which rapidly become refractory to treatment and result in brain damage. Current therapies have only a narrow time frame for effective administration after poisoning. 5-HT1A agonists were tested for efficacy in mice against a seizure-producing combination of the carboxylesterase inhibitor 2-(o-cresyl)-4H-1: 3: 2-benzodioxaphosphorin-2-oxide (CBDP) and sarin, producing an LD20-40. Administration of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) decreased glial fibrillary acidic protein (GFAP) staining in mice when administered 1min after CBDP and sarin while other 5-HT1A agonists buspirone and S-14506 were not effective. The reduction in GFAP staining by 8-OH-DPAT remained significant when a single dose was administered two hours after the toxic challenge. In addition, 8-OH-DPAT reversed the increase in the inflammatory factor IL-1β in the dentate gyrus and amygdala but did not reduce positive TUNEL staining in the dentate gyrus. Due to the failure of the two other agonists to provide protection, the 5-HT1A antagonist WAY-100635 was tested. WAY-100635 was found to neither reverse the neuroprotective effects of 8-OH-DPAT nor worsen the damage when given alone, making a role for this receptor unlikely. The neuroprotective effects of 8-OH-DPAT appear to lie within its secondary pharmacology.
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ABSTRACT: The aim of the present study was to evaluate the neuroprotective effect of the 5-hydroxytryptamine1A (5-HT1A) agonists, CM 57493 and urapidil, in vivo and in vitro, respectively. In vivo permanent occlusion of the middle cerebral artery (MCA) was performed in male Wistar rats. Forty-eight hours after electrocoagulation of the MCA the infarct volume was determined. Pretreatment of the rat with the 5-HT1A agonist urapidil significantly reduced infarct development. The neuroprotective effect of the agent was restricted to the cortical area; the striatal damage was not influenced. As the stimulation of the 5-HT1A receptor by serotonin is supposed to induce inhibitory, hyperpolarizing effects by opening of a Ca(2+)-independent neuronal K+ ionophore, the efficacy of agonistic drugs directly on the neuron was investigated in vitro. Cyanide-induced cytotoxic hypoxia as well as glutamate-induced excitotoxicity were performed using primary neuronal cell cultures from chick embryo cerebral hemispheres. Treatment with the 5-HT1A agonists urapidil and CM 57493 significantly increased protein content of hypoxic cultures. CM 57493 added to the culture medium (1-10 microM) during and up to 24 h after glutamate exposure ameliorated viability of the neurons. The results demonstrate neuroprotective potency of the 5-HT1A agonists, urapidil and CM 57493, when applied under hypoxic, excitotoxic and ischemic conditions in vivo and in vitro, respectively. Both, presynaptically induced inhibition of glutamate release as well as postsynaptically induced inhibition of neuronal excitability could be discussed as possible mechanisms of action of the 5-HT1A receptor agonism.Journal of Neural Transmission - Parkinson s Disease and Dementia Section 02/1994; 8(1-2):73-83. DOI:10.1007/BF02250918
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ABSTRACT: Anticholinergics, benzodiazepines and N-methyl-D-aspartate (NMDA) antagonists have been shown to modulate the expression of nerve agent-induced seizures. This study examined whether the anticonvulsant actions of these drugs varied depending on the duration of prior seizure activity. Rats implanted with electrodes to record electroencephalographic (EEG) activity were pretreated with the oxime HI-6 (125 mg/kg, IP) to prolong survival, and then challenged with a convulsant dose of the nerve agent soman (180 micrograms/kg, SC); treatment compounds (scopolamine, diazepam, MK-801, atropine, benactyzine, and trihexyphenidyl) were delivered IV at specific times after seizure onset. Both diazepam and MK-801 displayed a similar profile of activity: At both short or long times after seizure initiation the anticonvulsant efficacy of each drug remained the same. Diazepam, and especially MK-801, enhanced the lethal actions of soman by potentiating the respiratory depressant effects of the agent; scopolamine given prior to diazepam or MK-801 protected against the respiratory depression. Scopolamine and atropine showed a dose- and time-dependent effectiveness; the longer the seizure progressed the higher the dose of drug required to terminate the seizure, with eventual loss of anticonvulsant activity if the seizure had progressed for 40 min. In contrast, benactyzine and trihexyphenidyl showed a third profile of activity: There was a smaller increase in drug dosage required for anticonvulsant activity as seizure duration increased, and both drugs could terminate seizures that had progressed for 40 min. The early anticonvulsant action of anticholinergics is interpreted as a specific effect that blocks the primary cholinergic excitatory drive that initiates, and first maintains, nerve agent seizures. If allowed to progress, the seizure activity itself recruits excitatory neurotransmitter systems (i.e., NMDA) that eventually maintain the seizure independent of the initial cholinergic drive. This is indicated by the eventual ineffectiveness of scopolamine and atropine as the duration of the seizure progresses. Diazepam and MK-801 appear to act to moderate nerve agent seizures by enhancing inhibitory activity (diazepam) or dampening the secondarily activated noncholinergic excitatory system (MK-801). Benactyzine and trihexyphenidyl represent compounds that possibly have both anticholinergic and NMDA antagonistic properties.Neuroscience & Biobehavioral Reviews 02/1993; 17(2):203-15. DOI:10.1016/S0149-7634(05)80151-4 · 10.28 Impact Factor
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ABSTRACT: An intron-containing gene encoding a novel human serotonin (5-HT) receptor was isolated from human genomic and cDNA libraries with probes directed to transmembrane regions of the adenylate cyclase stimulatory Drosophila serotonin receptor gene, 5-HTdrol. Membranes harvested from transiently transfected Cos-7 cells displayed high affinity (Kd = 8.5 nM), saturable (Bmax = 6.6 pmol/mg protein) [3H]5-HT binding. The rank order of potencies for serotonergic ligands to displace specific [3H]5-HT binding was: 5-carboxamido-tryptamine > methiothepin > metergoline > 5-HT > 8-hydroxy-2-(di-n-propylamino)tetralin > sumatriptan > ketanserin > zacopride. 5-HT produced a dose-dependent (EC50 = 992 nM) stimulation (approximately 20-fold) of cAMP accumulation in transiently transfected cells, and this response was antagonized by the nonselective 5-HT antagonist methiothepin. RNA for this gene was predominantly detected in the human brain and a subset of peripheral tissues including coronary artery and several tissues of the gastrointestinal tract. The molecular biological and pharmacological properties of this receptor suggest that it is the first member of a new serotonin receptor subfamily (5-HT7). The second messenger coupling, and tissue distribution indicate a possible identity to 5-HT receptors that mediate relaxant responses in certain isolated blood vessels.Journal of Biological Chemistry 11/1993; 268(31):23422-6. · 4.57 Impact Factor