Abstract
We demonstrated that capsaicin (CAP), an agonist of transient receptor potential vanilloid subtype 1 (TRPV1), inhibits microglia activation and microglia-derived oxidative stress in the substantia nigra (SN) of MPP+-lesioned rat. However, the detailed mechanisms how microglia-derived oxidative stress is regulated by CAP remain to be determined. Here we report that ciliary neurotrophic factor (CNTF) endogenously produced by CAP-activated astrocytes through TRPV1, but not microglia, inhibits microglial activation and microglia-derived oxidative stress, as assessed by OX-6 and OX-42 immunostaining and hydroethidine staining, respectively, resulting in neuroprotection. The significant increase in levels of CNTF receptor alpha (CNTFRα) expression was evident on microglia in the MPP+-lesioned rat SN and the observed beneficial effects of CNTF was abolished by treatment with CNTF receptor neutralizing antibody. It is therefore likely that CNTF can exert its effect via CNTFRα on microglia, which rescues dopamine neurons in the SN of MPP+-lesioned rats and ameliorates amphetamine-induced rotations. Immunohistochemical analysis revealed also a significantly increased expression of CNTFRα on microglia in the SN from human Parkinson’s disease patients compared with age-matched controls, indicating that these findings may have relevance to the disease. These data suggest that CNTF originated from TRPV1 activated astrocytes may be beneficial to treat neurodegenerative disease associated with neuro-inflammation such as Parkinson’s disease.
Highlights
Microglia are the resident macrophages in the brain and spinal cord [1]
The present study demonstrates that ciliary neurotrophic factor (CNTF) originated from Transient receptor potential vanilloid subtype 1 (TRPV1) activated astrocytes inhibits microglial activation and activated microglia-derived oxidative stress through CNTFRα on microglia and rescues DA neurons in the substantia nigra (SN) of MPP+-lesioned rats, an animal model of Parkinson’s disease (PD) (Figure 7)
This hypothesis was further confirmed and strongly supported by the present data showing that the CAP-induced neuro-protection and behavioral recovery attained through inhibiting microglia-derived oxidative stress are abolished by genetic knockdown of TRPV1 with shTRPV1 [13]
Summary
Microglia are the resident macrophages in the brain and spinal cord [1]. Many studies have demonstrated that activated microglia play a pivotal role in the cause and progression of Parkinson’s disease (PD) characterized by the loss of dopamine (DA) neurons in the substantia nigra (SN) and motor dysfunctions [2,3,4,5]. Microglia-derived oxidative stress and inflammation are involved in degeneration of DA neurons in the SN of patients with PD [3,4,5,6,7,8] and in the 1-methyl-4-phenylpyridinium (MPP+)-lesioned rats [9]. We recently showed that TRPV1 activation by CAP contributes to DA neuronal survival by inhibiting microglia-derived oxidative stress in the MPP+-lesioned SN [9]. The study demonstrated that pharmacological inhibition of TRPV1 activation by the TRPV1 antagonist capsazepine attenuated CAP-induced neuro-protection and inhibition of microglia-derived ROS production, indicating TRPV1-dependent effects of CAP. Pharmacological blockade by capsazepine or genetic deficiency of TRPV1 did not influence CAP-induced suppression of the production of prostaglandin 2 (PGE2), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and free radical formation in activated microglia and macrophages [16,17,18]
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