Metaphit

Interaction of Delta sleep-inducing peptide and valproate on metaphit audiogenic seizure model in rats.[Pubmed:17957464]

Cell Mol Neurobiol. 2007 Nov;27(7):923-32.

Effects of valproate (VPA), a conventional antiepileptic drug and natural delta sleep-inducing peptide (DSIP) on Metaphit (1-[1-(3-isothiocyanatophenyl)-cyclohexyl]-piperidine)-induced audiogenic reflex epilepsy were studied. For the purpose of the study, valproate in the doses of 50 or 75 mg/kg and DSIP (1.0 mg/kg) was i.p. injected either alone or in combination to adult Wistar male rats with fully developed Metaphit seizures after eight audiogenic testing. The animals were stimulated using an electric bell (100 +/- 3 dB and 5-8 kHz, for 60 s) 60 min after Metaphit injection and afterwards at hourly intervals during the experiment. For EEG recording and power spectra analysis, three gold-plated screws were implanted into the scull. In EEGs of Metaphit-treated animals polyspikes, spike-wave complexes and sleep-like patterns were recorded, while the power spectra were increased. Combined treatment of Metaphit-induced seizures with valproate and DSIP was more effective than drugs alone especially during 4 h after administration. None of the applied dose combinations eliminated the EEG signs of Metaphit-provoked epileptiform activity. Taken together, the results of the present study suggest that the combinations of valproate and DSIP should be considered as beneficial polytherapy in Metaphit model of epilepsy.

Moderate body hypothermia alleviates behavioral and EEG manifestations of audiogenic seizures in metaphit-treated rats.[Pubmed:18066104]

Can J Physiol Pharmacol. 2007 Oct;85(10):1032-7.

We investigated the effects of hypothermia on the incidence and EEG signs of audiogenic seizures in rats treated with Metaphit (1-[1(3isothiocyanatophenyl)-cyclohexyl] piperidine), an experimental model of generalized reflex epilepsy. After i.p. injection with Metaphit (10 mg/kg) Wistar rats were exposed to audiogenic stimulation at hourly intervals during the time course of the experiment. After intermittent use of an ice pack 8 h after the Metaphit treatment, when seizure was fully developed, the body temperature was reduced to 30 +/- 0.5 degrees C in one half of the rats, and maintained at 37 +/- 0.5 degrees C in the other half. Saline-injected rats served as a control group. In the hypothermia group, the incidence of audiogenic seizures induced by Metaphit was completely suppressed during the 3 consecutive testing times, while no signs of epileptiform activity were noted in EEG tracings. The termination of hypothermic treatment resulted in the recovery of seizure susceptibility, and during audiogenic stimulation, bursts of spiking activity were recorded in the EEGs of Metaphit-treated rats. These findings indicate that moderate body hypothermia is an effective anticonvulsant treatment for audiogenic seizures in Metaphit-treated rats.

[Delta sleep-inducing peptide and its analogues alleviate the severity of metaphit-induced audiogenic seizures in rats].[Pubmed:18265587]

Med Pregl. 2007 Sep-Oct;60(9-10):436-40.

INTRODUCTION: We investigated the potential of delta sleep-inducing peptide (DSIP) and its analogue DSIP-12 (a nonapeptide with alanine in position 2 of DISP molecule substituted by beta-alanine) and tetrapeptide analogue DSIP1-4, to antagonize Metaphit(1-1 (3-isothiocyanatophenl)-cvyclohexyl piperidine) induced generalized reflex audiogenic seizures in adult male Wistar albino rats. MATERIAL AND METHODS: Five groups of adult male Wistar rats were intraperitoneally treated with: (1) saline; (2) Metaphit: (3) Metaphit + DSIP, (4) Metaphit + DSIPI-4 and (5) Metaphit + DSIP-12. To examine the blocking effects of DSIP and its analogues on fully developed Metaphit seizures, in the last three groups they were administered 8h after Metaphit injection. The rats were stimulated using an electric bell (1003 dB, 5-8 kHz, 60 s) one hour after Metaphit injection and afterwards at hourly intervals during the experiment. For EEG recordings and power spectra three gold-plated screws were implanted into the skull. RESULTS: In Metaphit-treated animals EEGs appeared as polyspikes and spike-wave complexes, while power spectra were increasing. The incidence and severity of netaphit-induced audiogenic seizures reached a peak value at 7-12 h after injection. Both DSIP and DSIP analogues significantly increased power spectra of delta waves and decreased the incidence of seizures, as well as mean seizure grade and tonic component of Metaphit-induced convulsions. CONCLUSION: Taken together, these results suggest that DSIP and its analogues should be considered as potential antiepileptic agents.

Anticonvulsant, but not antiepileptic, action of valproate on audiogenic seizures in metaphit-treated rats.[Pubmed:17714087]

Clin Exp Pharmacol Physiol. 2007 Oct;34(10):1010-5.

1. The blocking effects of valproate (2-propylpentanoic acid), a standard anti-epileptic drug, on Metaphit (1-[1-(3-isothiocyanatophenyl)-cyclohexyl]-piperidine)-induced audiogenic seizures as a model of generalized, reflex audiogenic epilepsy in adult Wistar male rats were studied. 2. Rats were stimulated using an electric bell (100 +/- 3 dB, 5-8 kHz, 60 s) 60 min after i.p. Metaphit (10 mg/kg) injection and afterwards at hourly intervals. For power spectra and electroencephalograph (EEG) recordings, three gold-plated screws were implanted into the skull. Different doses of valproate (50, 75 and 100 mg/kg) were injected i.p. into rats with fully developed Metaphit seizures after the eighth audiogenic testing. 3. In Metaphit-treated animals, the EEG appeared as polyspikes, spike-wave complexes and sleep-like patterns, whereas the power spectra were increased compared with the corresponding controls. 4. Valproate reduced the incidence and intensity of convulsions and prolonged the duration of the latency period in a dose-dependent manner 4 h after administration. 5. The ED(50) of valproate in the first hour after injection was 63.19 mg/kg (95% confidence interval 51.37-77.71 mg/kg). 6. None of the doses of valproate applied eliminated the EEG signs of Metaphit-provoked epileptiform activity. 7. Taken together, these results suggest that all doses of valproate examined acted to suppresse behavioural but not epileptic EEG spiking activity in Metaphit-induced seizures.

Effect of metaphit on dopaminergic neurotransmission in rat striatal slices: involvement of the dopamine transporter and voltage-dependent sodium channel.[Pubmed:1662274]

J Pharmacol Exp Ther. 1991 Dec;259(3):1188-96.

Metaphit, an isothiocyanate analog of phencyclidine (PCP), increased the basal release of radioactivity (outflow) from perfused rat striatal slices preloaded with [3H]dopamine above levels observed with the dopamine uptake blocker nomifensin. Preperfusing the slices with Metaphit, followed by its removal, attenuated the amphetamine- or dopamine-induced outflow. In slices prepared from reserpine-pretreated rats, the Metaphit (100 microM)-induced outflow was reduced to that observed with 10 microM nomifensin, suggesting a vesicular releasing effect of Metaphit in addition to dopamine uptake blockade. Electrically induced overflow of radioactivity from normal slices was stimulated by nomifensin and PCP, and by Metaphit at 3 microM; it was unaffected by Metaphit at 10 and 25 microM, and inhibited by higher concentrations of Metaphit. Evidence that the latter effect is due to blockade of voltage-dependent sodium channels is as follows. First, Metaphit, as did PCP, inhibited the binding of [3H]batrachotoxinin A 20-alpha benzoate to rat striatal synaptoneurosomes by increasing its dissociation rate; the effect of PCP, but not that of Metaphit, was reversible by washing. Second, Metaphit, as did PCP, inhibited veratridine (5 microM)-induced influx of [14C]guanidinium ion into synaptoneurosomes. Third, Metaphit inhibited overflow of radioactivity from [3H]dopamine-preloaded slices induced by 2.5 microM veratridine, as did the sodium channel blocker tetrodotoxin.

Metaphit, an isothiocyanate analog of PCP, induces audiogenic seizures in mice.[Pubmed:2548879]

Eur J Pharmacol. 1989 Jun 8;165(1):155-9.

Metaphit induces audiogenic seizures in mice. The most severe clonic/tonic seizures occur 18-24 h after Metaphit administration. After 48 h the incidence of the seizure episodes begin to diminish. These audiogenic seizures can be prevented by the administration of either PCP or MK-801 24 h after Metaphit and 30 min prior to audio stimulation. These seizures may be due to a modulation of the PCP recognition site by Metaphit which results in an enhanced probability that the NMDA/PCP ion channels are open.

Metaphit, an acylating ligand for phencyclidine receptors: characterization of in vivo actions in the rat.[Pubmed:3018219]

J Pharmacol Exp Ther. 1986 Sep;238(3):1101-7.

Metaphit, which acylates phencyclidine (PCP) receptors in vitro, was shown to acylate PCP receptors and antagonize the behavioral and electrophysiological effects of PCP in vivo. Metaphit (2 mumol/rat) administered i.c.v. produced PCP-like stereotyped behavior and ataxia in 10 to 20% of rats. At a lower dose, Metaphit (1 mumol/rat) antagonized the ability of PCP to induce stereotyped behavior and ataxia for 3 and 4 days, respectively. The Metaphit-induced antagonism of PCP induction of stereotyped behavior and ataxia was dose-dependent and specific as Metaphit did not antagonize induction of stereotyped behavior by amphetamine. Further evidence for a specific PCP receptor mechanism was the finding that PCP pretreatment blocked the effects of subsequent Metaphit administration. Metaphit also antagonized PCP-induction of stereotyped behavior, but not ataxia, after i.v. administration. Doses of Metaphit that produced long-term antagonism of the behavioral effects of PCP also produced a significant decrease in the maximum binding, but not Kd, of the binding of the PCP analog, [3H]-1-(2-thienyl)cyclohexyl]piperidine, in Metaphit-pretreated rats. The binding of [3H]etorphine and [3H]spiroperidol was not altered significantly by pretreating rats with Metaphit. (-)-Cyclazocine and (+)-SKF 10,047 induced stereotyped behavior and ataxia that was not antagonized by Metaphit-pretreatment. In electrophysiological experiments, Metaphit, like PCP, initially depressed the firing of caudate neurons as does PCP, but then irreversibly inhibited PCP-induced depression of caudate neurons. These results suggest that Metaphit antagonized the effects of PCP by selectively acylating PCP receptors and that (-)-cyclazocine- and (+)-SKF 10,047-induced behavioral effects are not mediated primarily by PCP receptors.

A specific acylating agent for the [3H]phencyclidine receptors in rat brain.[Pubmed:2982662]

FEBS Lett. 1985 Feb 25;181(2):318-22.

A derivative of phencyclidine (PCP, 1 in fig. 1) bearing an isothiocyanate moiety on the meta position of the aromatic ring (Metaphit, 3 in fig. 1) has been synthesized and identified as a rapid and specific site-directed acylating agent of the [3H]phencyclidine binding site in rat brain homogenates. The percentage of sites irreversibly inactivated by Metaphit was found to be the same in the hippocampus and striatum and the remaining sites were unaffected by Metaphit treatment under any conditions, suggesting that at least two distinct binding sites are present. An isomeric isothiocyanate derivative did not irreversibly inhibit [3H]phencyclidine receptors, indicating structural specificity for Metaphit in the inhibition of these receptors. The availability of Metaphit should greatly facilitate study of the structure and function of the phencyclidine receptors.