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

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. F 2 -isoprostanes (F 2 -IsoPs) and F 4 -neuroprostanes (F 4 -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 F 2 -IsoPs, F 4 -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 F 2 -IsoP, F 4 -NeuroPs and citrulline levels were found in mice pretreated with Vitamin E (α-tocopherol, 100 mg/kg, ip) for 3 days, or with N-tert-butyl-α-phenylnitrone (PBN, 200 mg/kg, ip) 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 F 2 -IsoPs and F 4 -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.

Hydroalcoholic extract ofEmblica officinalisprotects against kainic acid-induced status epilepticus in rats: Evidence for an antioxidant, anti-inflammatory, and neuroprotective intervention

“…KA-induced SE following systemic or intracerebroventricular injection of the drug initiates neuronal injury and death in different parts of the limbic systems (Montgomery et al, 1999). The mechanism involved in the pathogenesis appears to be linked to oxidative stress (Zaja-Milatovic et al, 2008). In various experimental studies, it has been demonstrated that antioxidants can prevent the excitotoxicity induced by agents such as glutamate and KA (Silva et al, 2008;Dong et al, 2009;Wu et al, 2009).…”

Naringin Protects against Kainic Acid-Induced Status Epilepticus in Rats: Evidence for an Antioxidant, Anti-inflammatory and Neuroprotective Intervention

“…12) In various experimental studies, it has been demonstrated that antioxidants can prevent the excitotoxicity induced by agents like glutamate and kainic acid. [13][14][15] Thus, antioxidants may have a potential role in preventing excitotoxicity induced seizure genesis.…”

Non-enzymatic cyclic oxygenated metabolites of adrenic, docosahexaenoic, eicosapentaenoic and α-linolenic acids; bioactivities and potential use as biomarkers

“…Studies were highly focused on the effect of antiinflammatory and antioxidant agents in brain upon injury by chemical adulteration, and viral or bacterial infections. Both types of agents showed to be effective in reducing F 4 -NeuroPs levels after injury, in particular in the cerebrum [42][43][44][45]. Levels of F 4 -NeuroPs in ischemicinduced rodent brain (cerebral cortex, hippocampus, gray matter) were also determined after α-lipoic acid treatment but no significant effect was found [46].…”

“…[ [43][44][45] ATM −/− and ATM +/+: forebrain and cerebellum Supplementation of EUK-189 is a low-molecular weight salen-manganese for 84 days.…”