The current study was aimed to characterize for the first time the alterations in the characteristic neuro-inflammatory markers triggered by
sarin exposure in the rat's brain, and to investigate its dependency on seizure duration. Centrally mediated
seizures are a common consequence of exposure to
organophosphates (OP) despite conventional treatment with
atropine and an
oxime. In the present study
midazolam, was used to control duration and intensity of
seizures. The levels of the pro-inflammatory
cytokine peptides IL-1beta,
IL-6,
TNF-alpha and
prostaglandin E2 (
PGE2) were monitored at various times after
sarin exposure in the hippocampus and cortex of rats treated with
midazolam following 5 or 30 min of seizure activity. Biochemical evaluation of brain tissues revealed a significant increase in the level of the pro-inflammatory
peptides starting at 2 h and peaking at 2-24 h following
sarin. Hippocampal values of IL1-beta increased from 1.2+/-0.1 pg/mg tissue (control), to 2.4+/-0.3 at 2 h (5 min seizure) and to 9.3+/-2.5 at 8h (30 min seizure).
PGE2 level in the hippocampus increased up to 24 h following exposure (from 56+/-3 to 175+/-26 and 277+/-28 pg/mg tissue) following 5 and 30 min of seizure activity respectively. Thus, unlike limitation of
seizures to 5 min by
midazolam,
delayed treatment (30 min) resulted in prolonged
seizures and pronounced increase in
cytokines and
PGE2. In addition, a second increase in inflammatory markers was observed 30 days following
sarin exposure only in rats treated following 30 min of seizure activity. Histological evaluation of the rat brain, conducted in this study, revealed lack of damage in the hippocampus and piriform cortex with minor lateral ventricles enlargement in few animals following 5 min of
sarin-induced seizure activity. In contrast, marked histological damage to the brain was demonstrated following 30 min of seizure activity, consisting severe damage to the hippocampus, piriform cortex and some thalamic nuclei. In summary, a novel characterization of the prolonged central neuro-inflammatory process that accompanies
sarin exposure is presented. The timing of the anticonvulsive treatment was shown to be crucial in modulation of the neuro-inflammatory response, and may implicate the consequent long-term brain damage.