Simvastatin Protects Against Lipopolysaccharide-induced Rat Dopaminergic Neuronal Injury And Its Mechanism

Objective:To examine the effect of simvastatin treatment on inflammation-mediateddopaminergic neuronal injury and its mechanism.Methods:Hemiparkinsonian rat models were established by stereotaxieal injection oflipopolysaccharide (LPS) in the right substantia nigra compacta (SNpc).Rats wererandomly divided into three groups: a sham-operated group, received an injection of sameamount of saline in the right SNpc after intraperitoneal injections with vehicle treatment for2days and1h before the surgery; a LPS-injected group after vehicle treatment, too; andLPS-injected groups receiving intraperitoneal injections with simvastatin for the same timeas the two other groups. After LPS (5ug/uL,2.0μL) was injected into the right SNpc, ratswere continuously treated with simvastatin for14days. After two weeks treatment,rotational behavior test will carry out as0.05mg/kg,s.c.apomorphine.The behavior of ratswas observed, and the expression of tyroxine hydroxylase(TH) neurons in the substantianigra(SN), as well as terminals from the striatum; tumor necrosis factor-α(TNF-a)，interleukin-1β(IL-1β) and induced nitric oxide synthase(iNOS) was observed by usingimmunohistochemistry, western blot and enzyme-linked immunosorbent assay.Results: The LPS-treated rats exhibited obvious apomorphine-inducd rotational cycles compared with the sham-operated group rats(P<0.01);simvastatin significantly improvedthe behavioral manifestation compared with the LPS group which just received vehicle(P<0.05).The numbers of TH-positive neurons on the ipsilateral and contralateral sides tothe injection were similar in sham-operated animals(P>0.05);Rats that received vehicletreatment after an LPS intranigral injection showed a marked loss of TH-positive neurons(P<0.01) and the terminals from the striatum;Simvastatin prevented the loss ofdopaminergic neuron bodies in the SN and terminals from the striatum (P<0.05), andinhibited the deleterious activation of microglia in the substantia nigra pars compacta ofLPS-treated rats(P<0.05). Further more simvastatin significantly reduce the excessiveproduction of TNF-a,IL-1βand iNOS(P<0.05), which released by activated microglia inLPS-treated rats.Conclusion: This study demonstrates that simvastatin possesses neuroprotective effects oninjured nigra-striatum dopaminergic neurons in a LPS-induced animal model of Parkinson’sdisease. The mechanisms underlying these effects may include its potent down-regulationof iNOS and subsequent proinflammatory cytokine release in LPS-activated microglia.