Functional Role of Inflammatory Cytokines and Antiinflammatory Molecules in Seizures and Epileptogenesis

Abstract

Summary: Purpose:We investigated the changes in the expression of proinflammatory cytokines and related molecules in the rodent hippocampus after the induction of limbic seizures. We then studied the effects of pharmacologic intervention on the interleukin (IL)-1 system on limbic seizures and the susceptibility to seizures of transgenic mice overexpressing the naturally occurring antagonist of IL-1 (IL-1Ra) in astrocytes.Methods: Limbic seizures were induced in rodents by intrahippocampal injection of kainic acid or bicuculline methiodide or by electrical stimulation of the hippocampus causing status epilepticus (SE). Seizure activity was recorded by EEG analysis and behavioral observation according to Racine's scale. Cytokine expression in the hippocampus was studied by reverse transcriptase-polymerase chain reaction (RT-PCR) followed by Southern blot quantification of the various messenger RNAs (mRNAs) and by immunocytochemistry.Results: We found that limbic seizures rapidly and transiently enhanced IL-1␤, IL-6, and tumor necrosis factor (TNF)-␣ mRNA in the hippocampus with a peak effect at 6 h after SE. Immunoreactivity of the various cytokines was increased in glia. The increase of IL-1Ra was delayed because the peak effect was observed at 24 h after SE. Moreover, IL-1Ra was not produced in large excess, as during peripheral inflammation but in a molar ratio to IL-1␤ of 1:1. Intrahippocampal injection of IL-1␤ worsened seizure activity, whereas IL-1Ra was a powerful anticonvulsant in various models of limbic seizures. Transgenic mice overexpressing IL-1Ra in astrocytes were less sensitive to bicuculline-induced seizures.Conclusions: This study shows that limbic seizures in rodents rapidly and reversibly induce proinflammatory cytokines in glia and suggests that changes in the IL-1Ra/IL-1␤ ratio in brain may represent an effective physiopathologic mechanism to control seizures.

Optimization of multiplexed bead-based cytokine immunoassays for rat serum and brain tissue

“…More frequently mRNA changes are reported (e.g., see Jankowsky and Patterson, 1999;Vezzani et al, 2002), which mirror our protein changes here. For example, mRNA's for IL-1β, IL-6 and TNF-α rise promptly after the induction of KA-induced seizures (Vezzani et al, 2002) though sham injected animals were not used for comparison. We show that 5 h after the induction of KA-induced seizures IL-1β is significantly elevated above sham controls, while IL-4, IL-10 and GM-CSF are significantly less.…”

“…Seizure activity raises brain tissue levels of various cytokines (Jankowsky and Patterson, 1999;Vezzani et al, 2002). Accordingly, we used a well-established animal model of temporal lobe epilepsy (TLE) (Avanzini et al, 1998) to illustrate the feasibility and utility of multiplexed immunoassays to detect cytokine changes from seizures or related injury in hippocampal tissue.…”

Interleukin-1β Biosynthesis Inhibition Reduces Acute Seizures and Drug Resistant Chronic Epileptic Activity in Mice

“…The last drug administration was followed by a 3-day wash-out period during which EEG was recorded daily from 9:00 am to 11:00 am; the time required by each epileptic mouse to recover its pre-injection baseline activity after drug withdrawal (after day 4 of treatment, i.e., the eighth drug administration) was used to estimate the duration of VX-765 anticonvulsant action. At the end of the pharmacological experiments with 50 mg/kg VX-765 (including the 3 day wash-out period), the epileptic mice (Table 1, numbers [10][11][12][13][14][15] were recorded continuously between 9:00AM and 5:00PM for , and on the following day, the epileptic mice received VX-765 twice a day (at 9:00AM and 4:00PM) for 4 consecutive days, and the EEG recording was done for 2 h after each drug administration. The last drug administration was followed by a 3-day wash-out period, and each day EEG was recorded (at 9:00AM to 11:00AM) to evaluate the time required by each epileptic mouse to recover its pre-injection baseline activity after drug withdrawal.…”

“…Paracrine and autocrine activation of this signaling by the brain application of IL-1β exacerbates kainic acid-or bicuculline-induced seizures in rats and mice [5,11,13], and lowers the seizure threshold in febrile seizure models [7,8]. Conversely, IL-1 receptor antagonist (the naturally occurring competitive antagonist of IL-1R1) mediates powerful anticonvulsant effects in rodents [6,[13][14][15] and mice over-expressing IL-1 receptor antagonist in astrocytes, or lacking IL-1R1, are intrinsically less susceptible to seizures [7,13]. These data indicate the important involvement of elevated brain IL-1β levels and the activation of IL-1R1 signaling in experimental seizures.…”

Cerebroprotective Functions of HO-2

“…Brain TNFα production is increased during seizures and contributes to neuronal death [122,125,126]. TNFα also directly targets the cerebral vasculature [44].…”