CD40 mediates seizure severity
Musto, A.E.1, T.Anderson1, J.Benfield1, G. Rasic1, A.Rana1, A.Feeshaye1 and R. Britten1
1Eastern Virginia Medical School, Norfolk, VA
Temporal lobe epilepsy (TLE) has no cure or effective treatment in a subset of patients. TLE is a product of underlying progressive complex biological events denominated limbic epileptogenesis (LE) which is notable for up-regulation of pro-inflammatory mediators in the hippocampus. While exact inflammatory pathways have not been identified to explain this association, studies have indicated that inflammation mediates initiation and maintenance of seizures by inducing neuronal hyper-excitability, interneuron damage, and aberrant post-synaptic formation. One inflammatory molecule of interest, CD40, mediates neurite organization during brain development, which could result in aberrant neuronal connectivity in TLE. This research aimed to determine if the presence of CD40 promotes seizure susceptibility using a pentylenetetrazol (PTZ)-induced seizure model. Adult male mice (25-30g) deficient of CD40 (CD40KO, n=7) and its respective age-gender control (WT, n=7) received intra-peritoneal PTZ administration (10mg/Kg) every five minutes until either the animals elicited tonic-clonic seizures or received a total of 60mg/kg of PTZ. Then, animals were euthanized and brain samples were processed for histological analysis. Seizure severity (Racine's score), latency, and seizure frequency were analyzed using Student's t test and Z-score. CD40KO mice demonstrated reduction of seizure severity at 40 mg/kg doses compared to WT mice (CD40KO Racine's score: 0.1+-0.14 SEM; WT Racine's score: 2.8 +-0.54 SEM; p=0.0003). CD40KO mice had increased seizure latency compared to WT mice at 50 mg/kg doses (CD40KO: 217sec; WT: 69 seconds). CD40KO showed a reduction in seizure frequency compared to WT mice at various doses of PTZ, especially at 20, 30, and 40 mg/kg (CD40KO: 0, 0, 14.28; WT: 28.85, 14.28, 85.7; p= 0.0075; p<0.0001; p=0.05, respectively). These preliminary observations demonstrated a statistically significant reduction in seizure susceptibility in the CD40KO mice, indicating that CD40 may play a role in propagating seizure development. Therefore, the CD40L-CD40 interaction could be an innovative target for an immuno-therapeutic approach for LE that could be expanded to other neurological disorders disruptive neuronal networks including Alzheimer's disease and post-traumatic stress disorder.