Neutralization of RANTES and Eotaxin Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson Disease

Abstract

Parkinson disease (PD) is second only to Alzheimer disease as the most common human neurodegenerative disorder. Despite intense investigation, no interdictive therapy is available for PD. Recent studies indicate that both innate and adaptive immune processes are active in PD. Accordingly, we found a rapid increase in RANTES (regulated on activation normal T cell expressed and secreted) and eotaxin, chemokines that are involved in T cell trafficking, in vivo in the substantia nigra pars compacta and the serum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. RANTES and eotaxin were also up-regulated in the substantia nigra pars compacta of post-mortem PD brains as compared with age-matched controls. Therefore, we investigated whether neutralization of RANTES and eotaxin could protect against nigrostriatal degeneration in MPTP-intoxicated mice. Interestingly, after peripheral administration, functional blocking antibodies against RANTES and eotaxin reduced the infiltration of CD4(+) and CD8(+) T cells into the nigra, attenuated nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. Therefore, we conclude that attenuation of the chemokine-dependent adaptive immune response may be of therapeutic benefit for PD patients.

Induction of Adaptive Immunity Leads to Nigrostriatal Disease Progression in MPTP Mouse Model of Parkinson’s Disease

“…Recently we have demonstrated that RANTES and eotaxin are rapidly induced in serum and nigra of MPTP-intoxicated mice and that neutralization of these two chemokines by functional blocking antibodies protects the nigrostriatum from MPTP toxicity (7). Here, to understand any possible relationship between spontaneous reversal of disease and RANTES/eotaxin, we examined the mRNA and protein levels of these chemokines in MPTP mouse model after 1d, 3d, 7d, 30d, and 60d of MPTP insult.…”

“…Although we observed some increase in different proinflammatory cytokines in the serum of hemiparkinsonian monkeys after 37 d of MPTP intoxication, marked increase was found for chemokines like RANTES and eotaxin in the serum of hemiparkinsonian monkeys as compared to control serum (6). Recently, we have demonstrated that RANTES and eotaxin are upregulated in MPTP-intoxicated mice as well as postmortem PD brains as compared to age-matched controls and that functional blocking antibodies against RANTES and eotaxin protects against nigrostriatal degeneration in MPTP-intoxicated mice (7), indicating the involvement of these two chemokines in parkinsonism. Microglia in the nigra of hemiparkinsonian monkeys, MPTP-intoxicated mice and postmortem PD brains express RANTES and eotaxin (6, 7), suggesting that microglia-derived RANTES and eotaxin is the source of these chemokines in the serum.…”

“…Recently, we have demonstrated that RANTES and eotaxin are upregulated in MPTP-intoxicated mice as well as postmortem PD brains as compared to age-matched controls and that functional blocking antibodies against RANTES and eotaxin protects against nigrostriatal degeneration in MPTP-intoxicated mice (7), indicating the involvement of these two chemokines in parkinsonism. Microglia in the nigra of hemiparkinsonian monkeys, MPTP-intoxicated mice and postmortem PD brains express RANTES and eotaxin (6, 7), suggesting that microglia-derived RANTES and eotaxin is the source of these chemokines in the serum. Since the upregulated levels of RANTES and eotaxin in serum and nigra of MPTP-intoxicated mice rapidly decreased with time, we decided to supplement these chemokines peripherally.…”

“…While pondering upon this important issue, we observed that even after 37 d of MPTP insult, serum and nigra of MPTP-intoxicated hemiparkinsonian monkeys contain very high level of RANTES and eotaxin (6). Recently, we have demonstrated rapid upregulation of RANTES and eotaxin in nigra and serum of MPTP-intoxicated mice (7). Furthermore, we have also shown that RANTES and eotaxin are upregulated in the SNpc of postmortem PD brains as compared to age-matched controls and that functional blocking antibodies against RANTES and eotaxin protects against nigrostriatal degeneration in MPTP-intoxicated mice (7), indicating the importance of these two chemokines in nigrostriatal pathology.…”

Thymoquinone increases the expression of neuroprotective proteins while decreasing the expression of pro-inflammatory cytokines and the gene expression NFκB pathway signaling targets in LPS/IFNγ -activated BV-2 microglia cells

“…The microglial clustering around neuritic plaques contribute the neuroinflammation, and progressive neurodegeneration and CCL5 down-regulation reduce chemotaxis of microglia toward Aβγaggregates (Huang et al, 2010). Furthermore, it has also been demonstrated that CCL5 is up-regulated in the substantia nigra of PD mouse models and the neutralization of CCL5 protects against nigrostriatal degeneration (Chandra et al, 2016). CXCL3 has also been found to be upregulated other disease states (Martín-Fuentes et al, 2009; See et al, 2014; Gui et al, 2016).…”