Carisbamate acutely suppresses spasms in a rat model of symptomatic infantile spasms

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Purpose: Infantile spasms are the signature seizures of West syndrome. The conventional treatments for infantile spasms, such as adrenocorticotropic hormone (ACTH) and vigabatrin, are not always effective, especially in symptomatic infantile spasms (SIS). We tested the efficacy of carisbamate, a novel neurotherapeutic drug, to suppress spasms in the multiple-hit rat model of SIS, and compared it with phenytoin to determine if its effect is via sodium-channel blockade. Methods: Sprague-Dawley rats received right intracerebral infusions of doxorubicin and lipopolysaccharide at postnatal day 3 (PN3) and intraperitoneal p-chlorophenylalanine at PN5. A single intraperitoneal injection of carisbamate was administered at PN4, after the onset of spasms, at the following doses: 10 mg/kg (CRS-10), 30 mg/kg (CRS-30), and 60 mg/kg (CRS-60), and was compared to vehicle-injected group (VEH). Video-monitoring of PN6-7 CRS-60 or VEH-injected pups was also done. Key Findings: Carisbamate acutely reduced both behavioral spasms (CRS-30 and CRS-60 groups only) and electroclinical spasms during the first 2-3 postinjection hours, without detectable toxicity or mortality. In contrast, phenytoin (20 or 50 mg/kg) failed to suppress spasms. Significance: Our findings provide preclinical evidence that carisbamate displays acute anticonvulsive effect on spasms through a sodium channel-independent mechanism. Because spasms in the multiple-hit rat model are refractory to ACTH and transiently sensitive to vigabatrin, carisbamate may constitute a candidate new therapy for SIS, including the ACTH-refractory spasms. Further confirmation with clinical studies is needed.

Original languageEnglish (US)
Pages (from-to)1678-1684
Number of pages7
JournalEpilepsia
Volume52
Issue number9
DOIs
StatePublished - Sep 2011

Fingerprint

Infantile Spasms
Spasm
Adrenocorticotropic Hormone
Vigabatrin
Sodium Channels
Phenytoin
Fenclonine
S-2-O-carbamoyl-1-o-chlorophenyl-ethanol
Intraperitoneal Injections
Doxorubicin
Sprague Dawley Rats
Lipopolysaccharides
Seizures
Mortality
Therapeutics

Keywords

  • Anticonvulsant
  • EEG
  • Phenytoin
  • Treatment
  • West syndrome

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Carisbamate acutely suppresses spasms in a rat model of symptomatic infantile spasms. / Ono, Tomonori; Moshe, Solomon L.; Galanopoulou, Aristea S.

In: Epilepsia, Vol. 52, No. 9, 09.2011, p. 1678-1684.

Research output: Contribution to journalArticle

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abstract = "Purpose: Infantile spasms are the signature seizures of West syndrome. The conventional treatments for infantile spasms, such as adrenocorticotropic hormone (ACTH) and vigabatrin, are not always effective, especially in symptomatic infantile spasms (SIS). We tested the efficacy of carisbamate, a novel neurotherapeutic drug, to suppress spasms in the multiple-hit rat model of SIS, and compared it with phenytoin to determine if its effect is via sodium-channel blockade. Methods: Sprague-Dawley rats received right intracerebral infusions of doxorubicin and lipopolysaccharide at postnatal day 3 (PN3) and intraperitoneal p-chlorophenylalanine at PN5. A single intraperitoneal injection of carisbamate was administered at PN4, after the onset of spasms, at the following doses: 10 mg/kg (CRS-10), 30 mg/kg (CRS-30), and 60 mg/kg (CRS-60), and was compared to vehicle-injected group (VEH). Video-monitoring of PN6-7 CRS-60 or VEH-injected pups was also done. Key Findings: Carisbamate acutely reduced both behavioral spasms (CRS-30 and CRS-60 groups only) and electroclinical spasms during the first 2-3 postinjection hours, without detectable toxicity or mortality. In contrast, phenytoin (20 or 50 mg/kg) failed to suppress spasms. Significance: Our findings provide preclinical evidence that carisbamate displays acute anticonvulsive effect on spasms through a sodium channel-independent mechanism. Because spasms in the multiple-hit rat model are refractory to ACTH and transiently sensitive to vigabatrin, carisbamate may constitute a candidate new therapy for SIS, including the ACTH-refractory spasms. Further confirmation with clinical studies is needed.",
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