Abstract
The present study examined whether crosstalk between cannabinoid (CB) and transient potential receptor vanilloid type 1 (TRPV1) could contribute to the survival of nigrostriatal dopamine neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD). MPTP induced a significant loss of nigrostriatal dopamine neurons and glial activation in the substantia nigra (SN) and striatum (STR) as visualized by tyrosine hydroxylase (TH) or macrophage antigen complex-1 (MAC-1) or glial fibrillary acidic protein (GFAP) immunocytochemistry, respectively. RT-PCR analysis shows the upregulation of inducible nitric oxide synthase, interleukin-1β, and tumor necrosis factor-α in microglia in the SN in vivo, indicating the activation of the inflammatory system. By contrast, treatment with capsaicin (a specific TRPV1 agonist) increased the survival of dopamine neurons in the SN and their fibers and dopamine levels in the STR in MPTP mice. Capsaicin neuroprotection is accompanied by inhibiting MPTP-induced glial activation and production of inflammatory cytokines. Treatment with AM251 and AM630 (CB1/2 antagonists) abolished capsaicin-induced beneficial effects, indicating the existence of a functional crosstalk between CB and TRPV1. Moreover, treatment with anandamide (an endogenous agonist for both CB and TRVP1) rescued nigrostriatal dopamine neurons and reduced gliosis-derived neuroinflammatory responses in MPTP mice. These results suggest that the cannabinoid and vanilloid system may be beneficial for the treatment of neurodegenerative diseases, such as PD, that are associated with neuroinflammation.
Highlights
Parkinson’s disease (PD) is a well-known neurodegenerative disorder that is characterized by the degeneration of dopamine neurons in the substantia nigra pars compacta (SNpc) and dopamine deficiency in the striatum (STR), resulting in motor dysfunction [1, 2]
We recently demonstrated that Transient receptor potential vanilloid subtype 1 (TRPV1) activation by CAP increased the survival of nigral dopamine neurons by modulating the M1/M2 microglia/macrophage phenotype in lipopolysaccharide- (LPS-) injected SN [10], indicating that TRPV1 is a possible therapeutic target to treat PD
Consistent with our previous reports [11, 18, 21], tyrosine hydroxylase (TH) immunohistochemical analysis reveals the significant loss of TH+ cells in the SN (Figure 1(b)) and TH+ fibers in the STR (Figure 3(a)) in MPTP-treated mice compared to phosphate-buffered saline (PBS)-treated control mice (Figures 1(b) and 3(a))
Summary
Parkinson’s disease (PD) is a well-known neurodegenerative disorder that is characterized by the degeneration of dopamine neurons in the substantia nigra pars compacta (SNpc) and dopamine deficiency in the striatum (STR), resulting in motor dysfunction [1, 2]. Recent evidence has shown that reactive microglia and astrocytes are known to play a crucial role in the production of proinflammatory mediators such as nitric oxide (NO), inducible nitric oxide synthase (iNOS), myeloperoxidase, and proinflammatory cytokines [5,6,7]. These inflammatory mediators are attributable to the degeneration of nigrostriatal dopamine neurons in animal models of PD and PD patients [3, 5, 7]. Current experimental studies, such as the development of neuroprotective agents on dopamine neurons through regulating glial activation and preventing production of neurotoxic inflammatory molecules, have provided opportunities to develop innovative strategies for PD therapy [5]
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