Pharmacologic suppression of oxidative damage and dendritic degeneration following kainic acid-induced excitotoxicity in mouse cerebrum

Snjezana Zaja-Milatovic, Ramesh C. Gupta, Michael Aschner, Thomas J. Montine, Dejan Milatovic

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Intense seizure activity associated with status epilepticus and excitatory amino acid (EAA) imbalance initiates oxidative damage and neuronal injury in CA1 of the ventral hippocampus. We tested the hypothesis that dendritic degeneration of pyramidal neurons in the CA1 hippocampal area resulting from seizure-induced neurotoxicity is modulated by cerebral oxidative damage. Kainic acid (KA, 1 nmol/5 μl) was injected intracerebroventricularly to C57Bl/6 mice. F2-isoprostanes (F2-IsoPs) and F4-neuroprostanes (F4-NeuroPs) were used as surrogate measures of in vivo oxidative stress and biomarkers of lipid peroxidation. Nitric oxide synthase (NOS) activity was quantified by evaluating citrulline level and pyramidal neuron dendrites and spines were evaluated using rapid Golgi stains and a Neurolucida system. KA produced severe seizures in mice immediately after its administration and a significant (p < 0.001) increase in F2-IsoPs, F4-NeuroPs and citrulline levels were seen 30 min following treatment. At the same time, hippocampal pyramidal neurons showed significant (p < 0.001) reduction in dendritic length and spine density. In contrast, no significant change in neuronal dendrite and spine density or F2-IsoP, F4-NeuroPs and citrulline levels were found in mice pretreated with vitamin E (α-tocopherol, 100 mg/kg, i.p.) for 3 days, or with N-tert-butyl-α-phenylnitrone (PBN, 200 mg/kg, i.p.) or ibuprofen (inhibitors of cyclooxygenase, COX, 14 μg/ml of drinking water) for 2 weeks prior to KA treatment. These findings indicate novel interactions among free radical-induced generation of F2-IsoPs and F4-NeuroPs, nitric oxide and dendritic degeneration, closely associate oxidative damage to neuronal membranes with degeneration of the dendritic system, and point to possible interventions to limit severe damage in acute neurological disorders.

Original languageEnglish (US)
Pages (from-to)621-627
Number of pages7
JournalNeuroToxicology
Volume29
Issue number4
DOIs
StatePublished - Jul 1 2008
Externally publishedYes

Keywords

  • Excitotoxicity
  • Isoprostanes
  • Neurodegeneration
  • Oxidative damage
  • Spine density

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

Fingerprint Dive into the research topics of 'Pharmacologic suppression of oxidative damage and dendritic degeneration following kainic acid-induced excitotoxicity in mouse cerebrum'. Together they form a unique fingerprint.

  • Cite this