ABSTRACT
Studies using in vitro Parkinson's disease (PD) models have found that lipopolysaccharide (LPS) induced reduction of connexin 43 (Cx43) gap junction communication and elevation of hemichannel function, which could cause neurotoxicity directly and indirectly via excessive ATP and glutamate release. However, in vivo study about Cx43 expression and function, as well as the efficacy of Cx43 inhibition for neuronal survival in PD is lacking. This study aimed to unravel the role of Cx43 in PD and understand the underlying mechanisms using an in vivo PD model. Male C57BL/6 mice received intranigral injection of LPS (5 µg) and 43Gap27 (4 µg), a Cx43 inhibitor, simultaneously. Results showed that following LPS treatment, total Cx43 expression decreased by about 60%, but the relative level of phosphorylated Cx43 increased to about double that controls (all p < 0.05). The administration of 43Gap27 significantly attenuated the loss of dopaminergic neurons and restored dopamine and its metabolites levels. Moreover, 43Gap27 treatment inhibited intense microgliosis and astrogliosis in nigrostriatal system induced by LPS and also ameliorated elevated levels of inflammatory mediators. Interestingly, Cx43 inhibition also increased nerve growth factors. In conclusion, Cx43 inhibition was able to prevent LPS-mediated dopaminergic neuronal death, possibly via neuroinflammation reaction reduction and neurotrophic factors elevation. Therefore, Cx43 may be a promising therapeutic target for degenerative neurological disorders such as PD.
Subject(s)
Connexin 43/antagonists & inhibitors , Connexins/therapeutic use , Dopaminergic Neurons/metabolism , Oligopeptides/therapeutic use , Parkinson Disease/drug therapy , Animals , Cell Death , Connexin 43/metabolism , Connexins/pharmacology , Dopaminergic Neurons/drug effects , Lipopolysaccharides/toxicity , Male , Mice , Mice, Inbred C57BL , Microglia/drug effects , Microglia/metabolism , Nerve Growth Factors/metabolism , Oligopeptides/pharmacology , Parkinson Disease/etiology , Parkinson Disease/metabolismABSTRACT
BACKGROUND: Previous work indicated that benzo[a]pyrene (B(a)P) exposure in utero might adversely affect neurodevelopment and cause Parkinson's Disease (PD)-like symptoms. However, the effect of utero exposure to B(a)P on PD-like α-synucleinopathy and the mechanism under are unclear. OBJECTIVE: The A53T human alpha-synuclein (α-syn) transgenic mice (M83+/-) were used in this study to gain insights into the role of B(a)P exposure in utero in the onset of α-syn pathology and neuronal damage. METHOD: Timed-pregnant M83+/- dams were exposed to 1) corn oil (vehicle) or 2) 5 mg/kg bw/d B(a)P or 3) 20 mg/kg bw/d B(a)P at gestational day 10-17 by oral gavage and then the SNCA transcription, α-syn accumulation and aggregation, neuroinflammation and nigral dopaminergic neurodegeneration of 60-day-old pups were evaluated. RESULT: SNCA mRNA and α-syn protein expression in the midbrain of 60 days adult mice were found to be remarkably elevated after B(a)P exposure in utero, the protein degradation capacity was injured (in 20 mg/kg dose group) and α-syn aggregation could be observed in the substantia nigra (SN); Enhanced Iba1 expression in the midbrain and microglial activation (in 20 mg/kg dose group) in the SN were also figured out; Besides, dopaminergic neurons in the SN of 60 days adult mice were significantly decreased. CONCLUSIONS: Our findings demonstrated that B(a)P exposure in utero could exacerbate α-syn pathology and induce activation of microglia which might further lead to dopaminergic neuronal loss in the SN.
Subject(s)
Benzo(a)pyrene/toxicity , Prenatal Exposure Delayed Effects/chemically induced , Prenatal Exposure Delayed Effects/genetics , Synucleinopathies/chemically induced , Synucleinopathies/genetics , alpha-Synuclein/genetics , Animals , Dose-Response Relationship, Drug , Female , Humans , Male , Mice , Mice, Transgenic , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/genetics , Parkinson Disease, Secondary/pathology , Pregnancy , Prenatal Exposure Delayed Effects/pathology , Synucleinopathies/pathologyABSTRACT
BACKGROUND: The underlying mechanism of viral infection as a risk factor for Parkinson's disease (PD), the second most common neurodegenerative disease, remains unclear. OBJECTIVE: We used Mac-1-/- and gp91phox-/- transgene animal models to investigate the mechanisms by which poly I:C, a mimic of virus double-stranded RNA, induces PD neurodegeneration. METHOD: Poly I:C was stereotaxically injected into the substantia nigra (SN) of wild-type (WT), Mac-1-knockout (Mac-1-/-) and gp91 phox-knockout (gp91 phox-/-) mice (10 µg/µl), and nigral dopaminergic neurodegeneration, α-synuclein accumulation and neuroinflammation were evaluated. RESULT: Dopaminergic neurons in the nigra and striatum were markedly reduced in WT mice after administration of poly I:C together with abundant microglial activation in the SN, and the expression of α-synuclein was also elevated. However, these pathological changes were greatly dampened in Mac-1-/- and gp91 phox-/- mice. CONCLUSIONS: Our findings demonstrated that viral infection could result in the activation of microglia as well as NADPH oxidase, which may lead to neuron loss and the development of Parkinson's-like symptoms. Mac-1 is a key receptor during this process.
