title: Lack of CCR5 modifies glial phenotypes and population of the nigral dopaminergic neurons, but not MPTP-induced dopaminergic neurodegeneration.
abstract: Constitutive expression of C-C chemokine receptor (CCR) 5 has been detected in astrocytes, microglia and neurons, but its physiological roles in the central nervous system are obscure. The bidirectional interactions between neuron and glial cells through CCR5 and its ligands were thought to be crucial for maintaining normal neuronal activities. No study has described function of CCR5 in the dopaminergic neurodegeneration in Parkinson's disease. In order to examine effects of CCR5 on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration, we employed CCR5 wild type (WT) and knockout (KO) mice. Immunostainings for tyrosine hydroxylase (TH) exhibited that CCR5 KO mice had lower number of TH-positive neurons even in the absence of MPTP. Difference in MPTP (15mg/kg×4 times, 2hr interval)-mediated loss of TH-positive neurons was subtle between CCR5 WT and KO mice, but there was larger dopamine depletion, behavioral impairments and microglial activation in CCR5 deficient mice. Intriguingly, CCR5 KO brains contained higher immunoreactivity for monoamine oxidase (MAO) B which was mainly localized within astrocytes. In agreement with upregulation of MAO B, concentration of MPP+ was higher in the substantia nigra and striatum of CCR5 KO mice after MPTP injection. We found remarkable activation of p38 MAPK in CCR5 deficient mice, which positively regulates MAO B expression. These results indicate that CCR5 deficiency modifies the nigrostriatal dopaminergic neuronal system and bidirectional interaction between neurons and glial cells via CCR5 might be important for dopaminergic neuronal survival.
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 712-749, Republic of Korea; College of Pharmacy, Chungbuk National University, 12 Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk, 361-763, Republic of Korea; Medical Research Center, Chungbuk National University, 12 Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk, 361-763, Republic of Korea.
authors.forename: Dong-Young
authors.initials: DY
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Chungbuk National University, 12 Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk, 361-763, Republic of Korea.
authors.forename: Myung Koo
authors.initials: MK
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chungbuk National University, 12 Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk, 361-763, Republic of Korea; Medical Research Center, Chungbuk National University, 12 Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk, 361-763, Republic of Korea. Electronic address: jinthong@chungbuk.ac.kr.
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000473:pathology / Q000502:physiology*; D006719:Homovanillic Acid / Q000378:metabolism; D020267:MPTP Poisoning / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000378:metabolism; D009043:Motor Activity / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000473:pathology / Q000503:physiopathology*; D009457:Neuroglia / Q000473:pathology / Q000502:physiology*; D019713:Receptors, CCR5 / Q000172:deficiency* / Q000235:genetics; D012720:Severity of Illness Index; D013378:Substantia Nigra / Q000473:pathology / Q000503:physiopathology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C000592874:CCR5 protein, mouse; D019713:Receptors, CCR5; D015102:3,4-Dihydroxyphenylacetic Acid; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase; D048051:p38 Mitogen-Activated Protein Kinases; D006719:Homovanillic Acid