Pharmacologic suppression of oxidative damage and dendritic degeneration following kainic acid-induced excitotoxicity in mouse cerebrum.
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 microl) 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 (alpha-tocopherol, 100mg/kg, i.p.) for 3 days, or with N-tert-butyl-alpha-phenylnitrone (PBN, 200mg/kg, i.p.) or ibuprofen (inhibitors of cyclooxygenase, COX, 14 microg/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.
Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, United States.
Snjezana
S
Zaja-Milatovic
Ramesh C
RC
Gupta
Michael
M
Aschner
Thomas J
TJ
Montine
Dejan
D
Milatovic
D000818:Animals; D054022:Cerebrum / Q000473:pathology*; D002956:Citrulline / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D004347:Drug Interactions; D005260:Female; D007839:Functional Laterality; D028421:Isoprostanes; D007608:Kainic Acid / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000150:complications / Q000209:etiology / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects
D028421:Isoprostanes; D018696:Neuroprotective Agents; D002956:Citrulline; D019001:Nitric Oxide Synthase; D007608:Kainic Acid