High-Dose Methotrexate Does Not Affect the Pharmacodynamics of Phenobarbital Hypnotic Action but Decreases the Central Nervous System (CNS) Sensitivity to Pentylenetetrazol-Induced Maximal Seizures in Rats

Amnon Hoffman*, Jose Alfon

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Chemotherapy with high-dose methotrexate (HD-MTX) is often associated with acute neurotoxicity. We determined whether the altered neuronal function after HD-MTX [such as the reduced regional cerebral metabolic glucose rate (rCMRGlc) and slow electroencephalographic pattern] affects the sensitivity of the CNS to centrally acting drugs: the depressant phenobarbital, which reduces rCMRGlc, and the analeptic agent pentylenetetrazol (PTZ), which elevates rCMRGlc. Adult male Sabra rats received an i.v. infusion of MTX, 0.51 mg/min, to induce neurotoxicity or saline solution for 24 hr. Subsequently, MTX-treated and control groups were infused in one experiment with phenobarbital until loss of the righting reflex and in the second experiment with PTZ until the onset of maximal seizures. HD-MTX did not affect the infused hypnotic dose or serum, brain, and cerebrospinal fluid concentrations of phenobarbital at the onset of anesthesia. The convulsive dose and PTZ concentrations in the serum and brain at the onset of maximal seizures were significantly higher in the HD-MTX-treated animals. These outcomes indicate that HD-MTX and the reduced rCMRGlc that follows this treatment do not contribute to the hypnotic action of phenobarbital. On the other hand, treatment with HD-MTX exhibited anticonvulsant properties as evidenced by the reduced CNS sensitivity to PTZ-induced seizures.

Original languageAmerican English
Pages (from-to)1295-1298
Number of pages4
JournalPharmaceutical Research
Volume9
Issue number10
DOIs
StatePublished - Oct 1992

Keywords

  • brain
  • brain glucose metabolism
  • drug interaction
  • high-dose methotrexate
  • induced seizures
  • neurotoxicity
  • pentylenetetrazol
  • pharmacodynamics
  • phenobarbital

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