Blockade of p75 Neurotrophin Receptor Reverses Irritability and Anxiety-Related Behaviors in a Rat Model of Status Epilepticus

Abstract

Background: Many recent epidemiological studies have shown that epileptic patients are more likely suffer from depression, anxiety, and irritability. However, the cellular mechanisms of epilepsy-induced psychotic behaviors are not fully elucidated. Neurotrophin receptors have been suggested to be involved in epilepsy and also in psychiatric disorders. Up-regulation of p75NTR expression and activation of p75NTR signalling cascades after the seizure have been shown, but the role of the p75 receptor in epilepsy-induced psychotic behaviors has not been documented so far. Therefore, the present work aimed to investigate the effect of p75 receptor blockade on seizure activity, irritability, and anxiety-like behaviors in a rat model of status epilepticus. Methods: Rats were injected with pilocarpine (350 mg/ kg, i.p.) to induce status epilepticus. Then various behavioral tests were performed after the blockade of p75NTR alone or in combination with p75 antagonist and phenobarbital. Molecular analysis by PCR was performed to investigate the expression of p75 and pro-NGF. Results: Molecular findings indicated a high level of mRNA expression for both p75 receptors and pro-NGF in the epileptic model group. Results also showed that the administration of p75 antagonist alone or in combination with phenobarbital was able to significantly influence the behavioral responses. Furthermore, 20-hours video monitoring showed a decrease in the frequency and duration of seizures in the rat group receiving p75 antagonist. Conclusion: Taken together, the present study suggests that the blockade of the p75 receptor may affect the irritability and anxietyrelated behavior in a rat model of status epilepticus.

The emerging role of furin in neurodegenerative and neuropsychiatric diseases

“…Similar to the changes in BDNF, Ngf mRNA increases in the hippocampus and neocortex of rats with limbic seizures [ 279 ]. The secreted proNGF is considered as a pathophysiological death-inducing ligand [ 280 ], while blocking proNGF can inhibit neuronal loss after seizures [ 281 ]. Notch signaling is activated in KA-induced epileptic mice and in human epileptogenic tissues, while activation of Notch signaling further promotes neuronal excitation of CA1 pyramidal neurons [ 163 ].…”

“…Studies on animal models of epilepsy have proposed potential involvement of dysregulations of neurotrophins, such as BDNF, NGF and NT-3, in human epilepsy [276][277][278][279][280][281][282]. TLE patients with hippocampal sclerosis show increased mRNA levels of BDNF, NGF and NT-3 in granule cells of hippocampus, which are correlated with either hippocampal neuron loss or aberrant supragranular mossy fiber sprouting [276].…”