TY - JOUR
T1 - Neutralization of RANTES and eotaxin prevents the loss of dopaminergic neurons in a mouse model of Parkinson disease
AU - Chandra, Goutam
AU - Rangasamy, Suresh B.
AU - Roy, Avik
AU - Kordower, Jeffrey H.
AU - Pahan, Kalipada
N1 - Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2016/7/15
Y1 - 2016/7/15
N2 - 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 chemokinedependent adaptive immune response may be of therapeutic benefit for PD patients.
AB - 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 chemokinedependent adaptive immune response may be of therapeutic benefit for PD patients.
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U2 - 10.1074/jbc.M116.714824
DO - 10.1074/jbc.M116.714824
M3 - Article
C2 - 27226559
AN - SCOPUS:84978405476
SN - 0021-9258
VL - 291
SP - 15267
EP - 15281
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 29
ER -