DPP4 regulates the inflammatory response in a rat model of febrile seizures.

Febrile seizures (FS) are the most common seizure disorders in children aged 6 months to 5 years. Children suffering from complex FS have a high risk of developing subsequent temporal lobe epilepsy (TLE). Neuroinflammation is involved in the pathogenesis of FS although the mechanism remains unknown. Our previous study using the Whole Rat Genome Oligo Microarray determined that Dipeptidyl peptidase IV (DPP4) is potentially a related gene in FS rats. In this study, we demonstrated that DPP4 expression was significantly increased at both the protein and mRNA levels after hyperthermia induction. Sitagliptin, a specific enzyme inhibitor of DPP4, remarkably attenuated the severity of seizures in FS rats, and hyperthermia-induced astrocytosis was suppressed after DPP4 inhibition. Furthermore, sitagliptin significantly decreased the levels of the inflammatory cytokines IL-1ß, TNF-α, and IL-6 but not IL-10. In addition, sitagliptin prevented NF-κB activation by decreasing phosphorylation of the p65 subunit. Taken together, our findings demonstrate that DPP4 functions as a critical regulator of neuroinflammation in hyperthermia-induced seizures and the DPP4 inhibitor may be a viable option for FS therapeutics.

Searsia chirindensis reverses the potentiating effect of prenatal stress on the development of febrile seizures and decreased plasma interleukin-1ß levels.

It is estimated that more than 80% of patients with epilepsy live in developing countries with 50-60% of them being children. This high prevalence is perpetuated by low socio-economic challenges, poor health care facilities and lack of drug affordability. Searsia chirindensis formerly known as rhus chirindensis and commonly known as 'Red Current' is a popular traditional medicinal plant, which has been used to treat a number of illnesses such as heart complaints and neurological disorders. The aim of this study is to investigate the effects of S. chirindensis on the development of febrile seizure in a prenatally stressed rat. Febrile seizures were induced by administering lipopolysaccharide to 14-day-old rat pups followed by kainic acid. A subset of the rats was treated with Searsia after induction of febrile seizures. Interleukin-1ß (IL-1ß) levels were measured in plasma. Lipid peroxidation was determined in liver tissue. Our data shows that treatment with Searsia reduced interleukin-1ß levels in plasma of the febrile seizure rats and prevented lipid oxidation in the liver. Prenatal stress is dampened by the beneficial effects of Searsia on seizure development in rat pups. These results highlight the potentiating effects of Searsia in the reversal of febrile seizures and prenatal stress effects.

TRPV1 promotes repetitive febrile seizures by pro-inflammatory cytokines in immature brain.

Febrile seizure (FS) is the most common seizure disorder in children, and children with FS are regarded as a high risk for the eventual development of epilepsy. Brain inflammation may be implicated in the mechanism of FS. Transient receptor potential vanilloid 1 (TRPV1) is believed to act as a monitor and regulator of body temperature. The role of inflammation in synaptic plasticity mediation indicates that TRPV1 is relevant to several nervous system diseases, such as epilepsy. Here, we report a critical role for TRPV1 in a febrile seizure mouse model and reveal increased levels of pro-inflammatory factors in the immature brain. Animals were subjected to hyperthermia for 30 min, which generates seizures lasting approximately 20 min, and then were used for experiments. To invoke frequently repetitive febrile seizures, mice are exposed to hyperthermia for three times daily at an interval of 4h between every time induced seizure, and a total of 4 days to induce. Behavioral testing for febrile seizures revealed that a TRPV1 knock-out mouse model demonstrated a prolonged onset latency and a shortened duration and seizure grade of febrile seizure when compared with wild type (WT) mice. The expression levels of both TRPV1 mRNA and protein increased after a hyperthermia-induced febrile seizure in WT mice. Notably, TRPV1 activation resulted in a significant elevation in the expression of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α and HMGB1) in the hippocampus and cortex. These data indicate that the reduction of TRPV1 expression parallels a decreased susceptibility to febrile seizures. Thus, preventative strategies might be developed for use during febrile seizures.

The role of interleukin-1beta in febrile seizures.

Febrile seizures (FS) occur in children as a result of fever. Despite their prevalence, the pathophysiology of FS has remained unclear. Recent evidence from clinical and experimental studies has highlighted a potential role of immune generated products in the genesis of FS. Of particular interest are the pro-inflammatory cytokine, interleukin-1beta (IL-1beta) and its naturally occurring antagonist, interleukin 1 receptor antagonist (IL-1ra). Using a novel animal model of FS, involving the generation of physiological fever, we investigated the role of the IL-1beta/IL-1ra system in the genesis of FS. We found that animals with FS had increased hippocampal and hypothalamic IL-1beta compared to equally treated animals without FS, which was first evident at onset of FS in the hippocampus. There were no differences in IL-1ra levels. ICV IL-1beta increased the number of animals with FS while IL-1ra had an opposite anti-convulsant effect. The data from these studies, in combination with recent results from other laboratories, have established a putative role for the IL-1beta/IL-1ra system in the genesis of FS.

Causal links between brain cytokines and experimental febrile convulsions in the rat.

PURPOSE: Despite the prevalence of febrile convulsions (FCs), their pathophysiology has remained elusive. We tested the hypothesis that components of the immune response, particularly the proinflammatory cytokine interleukin-1beta (IL-1beta) and its naturally occurring antagonist interleukin-1 receptor antagonist (IL-1ra) may play a role in the genesis of FC. METHODS: Postnatal day 14 rats were treated with lipopolysaccharide (LPS; 200 microg/kg, i.p.) followed by a subconvulsant dose of kainic acid (1.75 mg/kg, i.p.). Brains were harvested at and 2 h after onset of FCs to measure brain levels of IL-1beta and IL-1ra. Separate groups of animals were given intracerebroventricular (ICV) injections of IL-1beta, or IL-1ra in an attempt to establish a causal relation between the IL-1beta/IL-1ra system and FCs. RESULTS: Animals with FCs showed increased IL-1beta in the hypothalamus and hippocampus but not in the cortex compared with noFC animals that also received LPS and kainic acid. This increase was first detected in the hippocampus at onset of FCs. No detectable difference in IL-1ra was found in brain regions examined in either group. When animals were treated with IL-1beta ICV, a dose-dependant increase was noted in the proportion of animals that experienced FCs, whereas increasing doses of IL-1ra, given to separate groups of animals, were anticonvulsant. CONCLUSIONS: Our results suggest that excessive amounts of IL-1beta may influence the genesis of FCs. This may occur by overproduction of IL-1beta, or by alteration in the IL-1beta/IL-1ra ratio in the brain after an immune challenge.