Effects of procaine hydrochloride, diazepam, and diphenylhydantoin on seizure development in cortical and subcortical structures in rats

Racine, R.; Livingston, Kenneth E.; Joaquin, Andrew

doi:10.1016/0013-4694(75)90260-6

Cited by 158 publications

(39 citation statements)

References 19 publications

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“…Although procaine is known to selectively increase limbic electrophysiologic activity in animals and anterior paralimbic perfusion in humans (Heynen et al, 1995;Ketter et al, 1996;Munson et al, 1970;Parekh et al, 1995;Post, 1981;Post et al, 1984;Racine et al, 1975Racine et al, , 1979Wagman et al, 1967), the lack of regional variation in IC 50 values suggests that the competition of procaine with [ 18 F]FP-TZTP binding sites is similar across the brain. Furthermore, these data suggest that procaine's limbic selectivity is most likely not a result of limbic muscarinic receptors having enhanced regional sensitivity to procaine over that of other brain regions.…”

Section: Discussionmentioning

confidence: 99%

“…Similar to GABA, procaine microinjection (6-20 mg) into rat nucleus basalis inhibits frontal cortical neuronal firing in response to conditioned stimuli (pairing with medial forebrain stimulation) (Rigdon and Pirch, 1984). Moreover, procaine selectively activates limbic structures electrophysiologically in rats (Munson et al, 1970;Racine et al, 1975Racine et al, , 1979Wagman et al, 1967). Utilizing 2-deoxyglucose methodology, lidocaine, a closely related amide local anesthetic, selectively activated limbic structures in rats (Post et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

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A Potential Cholinergic Mechanism of Procaine's Limbic Activation

Benson

Carson

Kiesewetter

et al. 2004

Neuropsychopharmacol

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The local anesthetic procaine, when administered to humans intravenously (i.v.), yields brief intense emotional and sensory experiences, and concomitant increases in anterior paralimbic cerebral blood flow, as measured by positron emission tomography (PET). Procaine's high muscarinic affinity, together with the distribution of muscarinic receptors that overlaps with brain regions activated by procaine, suggests a muscarinic contribution to procaine's emotional and sensory effects. This study evaluates the effects of procaine on cerebral muscarinic cholinergic receptors in the anesthetized rhesus monkey. Whole brain and regional muscarinic receptor binding was measured before and after procaine administration on the same day in three anesthetized rhesus monkeys with PET and the radiotracer 3-(3-(3[ 18 F]fluoropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([ 18 F]FP-TZTP), a cholinergic ligand that has preferential binding to muscarinic (M 2 ) receptors. On separate days each animal received six different doses of i.v. procaine in a randomized fashion. Procaine blocked up to B90% of [ 18 F]FP-TZTP specific binding globally in a dose-related manner. There were no regional differences in procaine's inhibitory concentration for 50% blockade (IC 50 ) for [ 18 F]FP-TZTP. Tracer delivery, which was highly correlated to cerebral blood flow in previous monkey studies, was significantly increased at all doses of procaine with the greatest increases occurring near procaine's IC 50 for average cortex. Furthermore, anterior limbic regions showed greater increases in tracer delivery than nonlimbic regions. Procaine has high affinity to muscarinic M 2 receptors in vivo in the rhesus monkey. This, as well as a preferential increase of tracer delivery to paralimbic regions, suggests that action at these receptors could contribute to i.v. procaine's emotional and sensory effects in man. These findings are consistent with other evidence of cholinergic modulation of mood and emotion.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Potential Cholinergic Mechanism of Procaine's Limbic Activation

Benson

Carson

Kiesewetter

et al. 2004

Neuropsychopharmacol

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“…In some models, interventions have been performed during the interval to see whether they decrease or delay the onset of spontaneous seizures. Kindling models have been used most for this purpose and suggests that diazepam (DZP), phenobarbital (PB), and valproate (VPA) have antiepileptogenic effects, whereas results are mixed with phenytoin (PHT), and carbamazepine (CBZ) has little or none (10)(11)(12)(13)(14)(15). Although laboratory models can be very helpful in elucidating mechanisms and pointing out drugs that are likely to have an antiepileptogenic effect, one needs to have clinical trials to confirm the effect in humans.…”

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confidence: 99%

Antiepileptogenesis and Seizure Prevention Trials with Antiepileptic Drugs: Meta‐Analysis of Controlled Trials

2001

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Summary:Purpose: To synthesize evidence concerning the effect of antiepileptic drugs (AEDs) for seizure prevention and to contrast their effectiveness for provoked versus unprovoked seizures.Methods: Medline, Embase, and The Cochrane Clinical Trials Register were the primary sources of trials, but all trials found were included. Minimal requirements: seizureprevention outcome given as fraction of cases; AED or control assigned by random or quasi-random mechanism. Single abstracter. Aggregate relative risk and heterogeneity evaluated using Mantel-Haenszel analyses; random effects model used if heterogeneity was significant.Results: Forty-seven trials evaluated seven drugs or combinations for preventing seizures associated with fever, alcohol, malaria, perinatal asphyxia, contrast media, tumors, craniotomy, and traumatic brain injury. Conclusions: Effective or promising results predominate for provoked (acute, symptomatic) seizures. For unprovoked (epileptic) seizures, no drug has been shown to be effective, and some have had a clinically important effect ruled out.

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“…Phenytoin, a drug that is very efficacious against CPS in humans, has repeatedly been suggested to be ineffective in amygdala-kindled rats (26-28). These negative findings (26)(27)(28) suggest that experiments in amygdalakindled rats are not capable of predicting drug efficacy in patients with partial seizures. In most such studies, only supramaximal current was used for stimulations.…”

Section: Discussionmentioning

confidence: 99%

Anticonvulsant Activity of Felbamate in Amygdala Kindling Model of Temporal Lobe Epilepsy in Rats

Właź¹,

Löscher

1997

Epilepsia

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Summary:Purpose: Previous studies have demonstrated that felbamate (FBM, 2-phenyl-1,3-propanediol dicarbamate) at nontoxic doses exerts potent anticonvulsant activity in a variety of animal epilepsy or seizure models. We further characterized the anticonvulsant activity of FBM by using the kindling model of temporal lobe epilepsy (TLE).Methods: The experiments were performed in fully kindled rats. The anticonvulsant effect of FBM was assessed by determining seizure severity, afterdischarge (AD) duration and seizure duration either at the focal seizure threshold, or after suprathreshold stimulation. In addition, the neurological performance of kindled rats after FBM administration was evaluated in the open field and by the rotorod test.Results: FBM at doses of 12.5-50 mg/kg, given intraperitoneally (i.p.) 60 min before testing, dose-dependently increased the AD threshold (ADT). The maximal effect was achieved after the highest dose tested and reached almost 600% of the control ADT. This dose of FBM significantly diminished other seizure parameters, e.g., seizure severity, seizure duration, and AD duration. When the rats were stimulated with suprathreshold current (500 PA) seizure severity was moderately but significantly reduced. No behavioral abnormalities were noted in kindled rats after administration of either of the doses.Conclusions: FBM potently increases the threshold for focal seizures and reduces seizure severity, seizure duration, and AD duration at doses that produce no adverse behavioral effects in amygdala-kindled rats. These data are thus compatible with clinical experience with FBM in TLE and substantiate that kindling is a good predictor of anticonvulsant activity against TLE. Key Words: Amygdala-Felbamate-Kindling.Felbamate (FBM, 2-phenyl-1,3-propanediol dicarbamate) is a novel broad-spectrum epileptic drug (AED) with a favorable safety profile. Preclinical animal studies have shown that felbamate exerts anticonvulsant activity in a variety of models of epilepsy or epileptic seizures ( I ,2). FBM was also active in kainate-, pilocarpine-, and lithium-pilocarpine-induced status epilepticus (SE) in rats (3,4) and inhibited corneally kindled seizures in rats (I). In addition to its antiepileptic activity, FBM has clear-cut antiischemic properties (5,6). Clinically, FBM was the first compound demonstrated to be highly effective in patients with Lennox-Gastaut syndrome (7), but it also displayed much efficacy against partial seizures (8,9). In adults with epilepsy, -70% of cases of complex partial seizures are refractory to the currently available AEDs (lo), which emphasizes the need to develop new and more effective therapeutic strategies. An animal model that is best suited for studying drug-resistant partial epilepsy with seizures secondarily generalized is the amygdala-kindled rat (1 I). To our knowledge no inforAccepted July 14, 1997. mation on the activity of FBM in this model has yet been published to date. Therefore, we determined the anticonvulsant profile of FBM in amygdala-kindled rats. We...

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Effects of procaine hydrochloride, diazepam, and diphenylhydantoin on seizure development in cortical and subcortical structures in rats

Cited by 158 publications

References 19 publications

A Potential Cholinergic Mechanism of Procaine's Limbic Activation

A Potential Cholinergic Mechanism of Procaine's Limbic Activation

Antiepileptogenesis and Seizure Prevention Trials with Antiepileptic Drugs: Meta‐Analysis of Controlled Trials

Anticonvulsant Activity of Felbamate in Amygdala Kindling Model of Temporal Lobe Epilepsy in Rats

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