Inhibition of prothrombin kringle-2-induced inflammation by minocycline protects dopaminergic neurons in the substantia nigra in vivo.
Prothrombin kringle-2 (pKr-2), a domain of prothrombin, can cause the degeneration of mesencephalic dopaminergic neurons through microglial activation. However, the chemical products that inhibit pKr-2-induced inflammatory activities in the brain are still not well known. The present study investigated whether minocycline, a semisynthetic tetracycline derivative, could inhibit pKr-2-induced microglial activation and prevent the loss of nigral dopaminergic (DA) neurons in vivo. To address this question, rats were administered a unilateral injection of pKr-2 in the substantia nigra in the presence or absence of minocycline. Our results show that pKr-2 induces the production of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and inducible nitric oxide synthase from the activated microglia. In parallel, 7 days after pKr-2 injection, tyrosine hydroxylase immunocytochemical analysis and western blot analysis showed a significant loss of nigral DA neurons. This neurotoxicity was antagonized by minocycline and the observed neuroprotective effects were associated with the ability of minocycline to suppress the expression of tumor necrosis factor-α, interleukin-1β, and nitric oxide synthase. These results suggest that minocycline may be promising as a potential therapeutic agent for the prevention of DA neuronal degeneration associated with pKr-2-induced microglial activation.
aNeurodegeneration Control Research Center bDepartment of Biochemistry and Molecular Biology, School of Medicine cDepartment of East-West Medicine, Graduate School of East-West Medical Science, Kyung Hee University, Seoul dSchool of Life Sciences and Biotechnology eDepartment of Food Science and Nutrition fInstitute of Life Science and Biotechnology gBrain Science and Engineering Institute, Kyungpook National University, Daegu, Korea.
Jin Han
JH
Nam
Eunju
E
Leem
Min-Tae
MT
Jeon
Young-Je
YJ
Kim
Un Ju
UJ
Jung
Myung-Sook
MS
Choi
Sungho
S
Maeng
Byung Kwan
BK
Jin
Sang Ryong
SR
Kim
D000704:Analysis of Variance; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects*; D004660:Encephalitis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D005260:Female; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D018082:Kringles; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D008911:Minocycline / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011516:Prothrombin / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D053583:Interleukin-1beta; D008840:Microfilament Proteins; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D011516:Prothrombin; D014446:Tyrosine 3-Monooxygenase; D008911:Minocycline