Dynamic Changes And Function Role Of Procalcitonin In Rats With Status Epilepticus

Background and Objective:Status epilepticus(SE)is a life-threatening neurological emergency with considerable associated mortality and morbidity.Currently,the treatment of status epilepticus relies primarily on traditional anticonvulsant drugs,such as benzodiazepines,phenobarbital,valproic acid,etc.However,after taking standard anticonvulsant therapy,one third of the patients still developed refractory status epilepticus(RSE)or super-refractory status epilepticus(S-RSE),leading to severe unfavorable outcomes.It is,therefore,of paramount importance to explore the underlying mechanism and provide a new therapeutic target for SE.Status epilepticus originates in the failure of seizure-termination mechanism or the initiation of seizure-prolonging mechanism.Previous studies have shown that the excessive activation of inflammation network played an important role in the initiation and prolongation of SE.However,the key regulatory molecules involved in the network remain unclear.Procalcitonin(PCT)is the precursor of calcitonin,which has been widely used as a biomarker for the diagnosis of sepsis.However,recent studies have shown that PCT was involved into the peripheral inflammatory cascade as a deleterious inflammatory mediator.And peripheral immunoneutralization of PCT was confirmed in animal experiments to decrease microglial activation,prevent Abeta-induced neurotoxicity,and improve behavioral performance in experimental models of Alzheimer disease,suggesting that PCT might also have a modulatory effect upon neuroinflammation.Recently,an observational cohort study revealed that the serum level of PCT measured at status epilepticus onset was independently associated with unfavorable outcomes.In this study,our aim was to investigate the origins and dynamic changes of serum PCT in a rat status epileptic model,further explore the modulatory effect of PCT on neuronal excitability and synaptic plasticity.Methods:Lithium-pilocarpine injection(i.p)was used to induce status epilepticus in adult male Sprague-Dawley rats.Elisa assay was performed to detect PCT,CRP,IL-6 and IL-1? in serum.qRT-PCR and Western-blot were performed to measure mRNA and protein levels of PCT in multiple tissues.Then,we utilized immunohistochemistry in the hippocampal section.In the end,whole-cell patch recording was used to examine changes of synaptic plasticity and neuronal excitability after bath perfusion of PCT in hippocampus.Neuronal surface GABAA receptor ?2,3 was also measured by Western-blot.Results:The serum PCT level prominently ascended at 5 minutes post SE,which was much more dramatic and earlier than the increase of serum CRP,IL-6 and IL-1?.And both qRT-PCR and Western-blot showed ubiquitous expression of PCT following SE in multiple tissues throughout the body.Moreover,a significant increase of PCT expression in the hippocampus was observed at 30 minutes post SE,and the expression of PCT increases along with prolonged SE.Immunohistochemistry further showed that the activated astrocytes in the dentate gyrus of hippocampus remarkably upregulated the expression of PCT upon SE challenge(30 minutes and 1 hour post SE).Then,whole-cell patch recording was performed to explore the possible role of PCT in regulating the excitability of neurons.Bath perfusion of PCT(0.1nM)increased both amplitude and frequency of spontaneous excitatory postsynaptic currents(sEPSC),raised the number of action potentials(APs),and reduced the paired-pulse ratio(PPR)of pyramidal neurons in CA1 region of hippocampus.Furthermore,the neuronal surface GABAA receptor ?2,3 decreased with the increased treatment of PCT in vitro.Conclusions:High concentration of serum PCT was produced by multiple tissues,which was associated with status epilepticus severity.It was also upregulated in the hippocampus during SE,and might increase the excitability of pyramidal neurons and change their synaptic plasticity.Furthermore,PCT induced hippocampal GABAA receptor endocytosis,which could contribute to seizure's pharmoco-resistance to benzodiazepines.Thus,our study might shed light on the role of procalcitonin on triggering and sustaining of status epilepticus.