CB2 receptor activation prevents glial-derived neurotoxic mediator production, BBB leakage and peripheral immune cell infiltration and rescues dopamine neurons in the MPTP model of Parkinson’s disease

Abstract

The cannabinoid (CB2) receptor type 2 has been proposed to prevent the degeneration of dopamine neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. However, the mechanisms underlying CB2 receptor-mediated neuroprotection in MPTP mice have not been elucidated. The mechanisms underlying CB2 receptor-mediated neuroprotection of dopamine neurons in the substantia nigra (SN) were evaluated in the MPTP mouse model of Parkinson's disease (PD) by immunohistochemical staining (tyrosine hydroxylase, macrophage Ag complex-1, glial fibrillary acidic protein, myeloperoxidase (MPO), and CD3 and CD68), real-time PCR and a fluorescein isothiocyanate-labeled albumin assay. Treatment with the selective CB2 receptor agonist JWH-133 (10 μg kg−1, intraperitoneal (i.p.)) prevented MPTP-induced degeneration of dopamine neurons in the SN and of their fibers in the striatum. This JWH-133-mediated neuroprotection was associated with the suppression of blood–brain barrier (BBB) damage, astroglial MPO expression, infiltration of peripheral immune cells and production of inducible nitric oxide synthase, proinflammatory cytokines and chemokines by activated microglia. The effects of JWH-133 were mimicked by the non-selective cannabinoid receptor WIN55,212 (10 μg kg−1, i.p.). The observed neuroprotection and inhibition of glial-mediated neurotoxic events were reversed upon treatment with the selective CB2 receptor antagonist AM630, confirming the involvement of the CB2 receptor. Our results suggest that targeting the cannabinoid system may be beneficial for the treatment of neurodegenerative diseases, such as PD, that are associated with glial activation, BBB disruption and peripheral immune cell infiltration.

A Novel Bibenzyl Compound (20C) Protects Mice from 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine/Probenecid Toxicity by Regulating the α-Synuclein–Related Inflammatory Response

“…On the other hand, astrocytes can induce microglial activation to further accelerate the progression of neuroinflammation (Fellner et al, 2011;Halliday and Stevens, 2011;Barbierato et al, 2013;Facci et al, 2014). Both BBB leakage and glial activation have been discovered in clinical and in in vivo studies (Reale et al, 2009;Halliday and Stevens, 2011;Chung et al, 2016). In this study, we found BBB injury with severe swelling of the astrocytic end-feet, which are largely activated microglia that became more amoeboidic by losing their ramifications, and activated astrocytes with enlarged bodies.…”

“…Furthermore, the brain has its own resident immune cells (microglia), which comprise 20% of glial cells in the central nervous system (CNS) and survey the brain for injuries (Chen and Palmer, 2008;Maguire-Zeiss and Federoff, 2010). Both the BBB and microglia have key roles in the development and progression of neuroinflammation, which is involved in the degeneration observed in PD (Chen and Palmer, 2008;Chung et al, 2016). BBB damage can lead to the recruitment of T lymphocytes to the CNS and cause an inflammatory response by inducing microglial activation (Chen and Palmer, 2008;Chung et al, 2016), increasing the production of inflammatory factors such as tumor necrosis .…”

“…Both the BBB and microglia have key roles in the development and progression of neuroinflammation, which is involved in the degeneration observed in PD (Chen and Palmer, 2008;Chung et al, 2016). BBB damage can lead to the recruitment of T lymphocytes to the CNS and cause an inflammatory response by inducing microglial activation (Chen and Palmer, 2008;Chung et al, 2016), increasing the production of inflammatory factors such as tumor necrosis . One-way analysis of variance was followed by Duncan's post hoc tests.…”

Exercise Reverses Dysregulation of T-Cell-Related Function in Blood Leukocytes of Patients With Parkinson's Disease

“…In addition, evidence has suggested that peripheral inflammation plays a role in the early stages of disease initiation and progression, including the development of preclinical non-motor symptoms (19). These findings are supported studies manipulating peripheral immune cells in mouse models of PD, whereby inhibiting immune cell infiltration can attenuate dopaminergic neuron loss (24,25). Together, these studies suggest that peripheral immune responses may contribute to the pathogenesis of PD, and modulation of the immune system may be beneficial in the treatment of PD.…”

Gap Junction Coupled Cells, Barriers and Systemic Inflammation

“…The substances that produce these processes induce glial activation and damage of different barriers leading to infiltration of peripheral immune cells. Several inflammatory mediators are proposed and in the Parkinson's disease ROS seem to be of importance [46]. Disruption or breakdown of the BRB is seen in diabetic retinopathy and neovascular AMD leading to macular edema and threatening visual acuity [47,48].…”