Anti-epileptogenesis And Neuroprotection Of Baicalin In Experimental Rodent Models Of Epilepsy

Epilepsy, one of the most common neurological disorders, is characterizedby recurrent, usually unprovoked, epileptic seizures, and followed with thecognitive, psychosocial, and social consequences.Epileptogenesis is a process in which various insults (such as brain insult,stroke, SE, the inflammatin in brain, and so on.) induce brain to generate acascade event, enhance the susceptivity of seizure and generate spontaneousrecurrent seizures.At present, drug treatment is still the main approach for epilepsy therapy.Despite the availability of a wide range of antiepileptic drugs (AEDs), aboutone-third of individuals with epilepsy still experience seizures that do notrespond to medication. Furthermore, currently available AEDs are mainlysymptomatic: they block seizures but do not affect the underlying pathology orthe progression of the disorder. Thus, an urgent need exists for developingeffective therapies.Our previous research found that severe seizures (status epilepticus, SE)were associated with an aberrant migration of newborn neurons into the dentate hilus. And we found that activated microglia may contributed to the aberrantmigration of newborn neurons in epileptic brain, and that minocycline (MC, aselective inhibitor of microglia activation) could be a potential drug to impedeseizure-induced aberrant migration of newborn neurons.In recent years, the research on medicinal plants is a hot point. Baicalin,one of the major flavonoids isolated from the dry roots of Scutellaria baicalensisGeorgi, has been found to possess anti-inflammatory, anti-apoptosis, andanti-oxidant effects. Baicalin can pass through blood-brain barrier andattenuated focal cerebral ischemic reperfusion injury and exertedneuroprotective effects. The constituent baicalin has been found to interact withthe BZ site of GABAA receptors and demonstrated to exert the anxiolytic-likeeffect. Based on the above, it is reasonable to hypothesize that baicalin may playa neuro-protective role in epileptic model and may have the anti-epileptogensisrole.Based on the supposition above, we design the following experiment toinvestigate the role of baicalin on epileptic models and hope to found newtherapies to modify the epileptic process.1The anticonvulsant and neuroprotective effects of baicalin onpilocarpine-induced epileptic model in ratsIn this study, we evaluated the effects of baicalin on Pilo induced epilepticmodel in rats. We pretreated baicalin (100mg/kg)30min before the Pilo（400mg/kg) administration, we observed the incidence of SE, latency to SEand mortality. And the rats were sacrificed to complete biochemical andhistological measurements at24h,72h after SE respectively.The results were as followings:1) Baicalin pretreatment delayed the onset of pilocarpine-induced SE andreduced the mortality.2) Baicalin pretreatment alleviated the levels of oxidative stress in hippocampal after seizure induced by pilocarpine.3) Baicalin pretreatment reversed the neuronal loss, decreased the numberof degenerating cells, and suppressed neuronal apoptosis in the rat hippocampusinduced by seizure. The mechanism of neuronal apoptosis may be associatedwith the down-regulation of caspase-3pathway.2Baicalin reduced epileptogenic processes and protected againstcognitive deficits following status epilepticusThen, we investigated the anti-epileptogenic effect of baicalin on Piloinduced SE. SE was induced by Li-PILO intraperitoneal (i.p.) injection, baicalinwas injected i.p. at1h before lithium and pilocarpine, respectively. After SE, theanimals received consecutive injection of baicalin or saline every day for14d oruntil the day of sacrifice. The protein expression of IL-1β and TNF-α wasdetermined by enzyme-linked immunosorbent assay (ELISA) at3day after SE.Neuronal loss and neurodegeneration were investigated using NeuN and FJBstaining at7d after SE. The number of reactive astrocytes and microglia weremeasured at7d after SE. SRSs were monitored using video monitoring from14d-28d after SE. Morris water was used to evaluate the cognitive function ofrats. Mossy fiber sprouting was studied using Timm’s staining after5weeks.And at this time, BrdU were stained to examine aberrant neurogenesis at hilus.The results were as followings:1) Baicalin reduced inflammatory cytokine expression at3day after SE.2) Baicalin decreased the density of the GFAP and Iba-1positive cells at7day after SE.3) Baicalin prevented neuronal degeneration induced by SE.4) Baicalin reduced the risk of recurrent seizures.5) Baicalin prevented spatial learning deficits induced by SE.6) Baicalin reduced the moss fiber sprout induced by SE. 3Baicalin regulated proliferation and neuronal differentiation ofneural stem cellsRat neural stem cells prepared from E14.5lateral ganglionic eminenceand neocortex were cultured for two passages. We then obsearved the effects ofbaicalin on prolification and differeitiation of NSC.The results were as following:1) Baicalin promoted the proliferation of NSC.2) Baicalin promoted neuronal differentiation but inhibited glialdifferentiation of NPCs3) Baicalin increased GABAergic differentiation of rat neural stem cells.4) Baicalin modulated the express of Mash1.