Early treatment with C1 esterase inhibitor improves weight but not memory deficits in a rat model of status epilepticus

Abstract Background Status epilepticus (SE) is a prolonged and continuous seizure that lasts for at least 5 minutes. An episode of SE in a healthy system can lead to the development of spontaneous seizures and cognitive deficits which may be accompanied by hippocampal injury and microgliosis. Although the direct mechanisms underlying the SE-induced pathophysiology remain unknown, a candidate mechanism is hyperactivation of the classical complement pathway (C1q-C3 signaling). We recently reported that SE triggers an increase in C1q-C3 signaling in the hippocampus that closely paralleled cognitive decline. Thus, we hypothesized that blocking activation of the classical complement pathway immediately after SE may prevent the development of SE-induced hippocampal-dependent learning and memory deficits. Methods Because C1 esterase inhibitor (C1-INH) negatively regulates activation of the classical complement pathway, we used this drug to test our hypothesis. Two groups of male rats were subjected to 1 hr of SE with pilocarpine (280-300 mg/kg, i.p.), and treated with either C1-INH (SE+C1-INH, 20 U/kg, s.c.) or vehicle (SE+veh) at 4, 24, and 48 hours after SE. Control rats were treated with saline. Body weight was recorded up to 23 days after SE. At this time, recognition and spatial memory were determined using novel object recognition (NOR) and Barnes maze (BM), respectively, as well as locomotion and anxiety-like behaviors using open field (OF). Histological and biochemical methods were used to measure hippocampal injury including cell death, microgliosis, and inflammation. Results One day after SE, both SE groups had a significant loss of body weight compared to controls (p 0.05). At 14 days post-SE, SE+C1-INH rats displayed higher mobility (distance travelled and average speed, p 0.05). Compared to vehicle-treated SE rats, SE+C1-INH rats had increased levels of C3 and microglia in the hippocampus, but lower levels of caspase-3 and synaptic markers. Conclusions These findings suggest that acute treatment with C1-INH after SE may have some protective, albeit limited, effects on the physiological recovery of rats’ weight and some anxiolytic effects, but does not attenuate SE-induced deficits in hippocampal-dependent learning and memory. Reduced levels of caspase-3 suggest that treatment with C1-INH may protect against cell death, perhaps by regulating inflammatory pathways and promoting phagocytic/clearance pathways.