Deleterious effects of minocycline in animal models of Parkinson's disease and Huntington's disease.
Minocycline has been shown to exert anti-inflammatory effects underlying its putative neuroprotective properties in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease and in the R6/2 mouse model of Huntington's disease (HD). However, contradictory results have recently been reported. We report deleterious effects of minocycline in two phenotypic (toxic) models of Parkinson's disease and HD in monkey and mouse. Of seven MPTP-intoxicated female cynomolgus monkeys (0.2 mg/kg, i.v. until day 15), three received minocycline (200 mg b.i.d.). While placebo-MPTP-treated animals displayed mild parkinsonism at day 15, the minocycline/MPTP-treated animals tended to be more affected (P = 0.057) and showed a greater loss of putaminal dopaminergic nerve endings (P < 0.0001). In the 3-nitropropionic acid (3-NP) mouse model of HD, minocycline (45 mg/kg i.p.) was administered 30 min before each i.p. injection of 3-NP (b.i.d., cumulated dose, 360 mg/kg in 5 days). Mice receiving minocycline exhibited a worsening of the mean motor score with a slower recovery slope, more impaired general activity and significantly deteriorated performances on the rotarod, pole test and beam-traversing tasks. The histopathological outcome demonstrated that minocycline-treated mice presented significantly more severe neuronal cell loss in the dorsal striatum. The effect of minocycline vs. 3-NP was also investigated on hippocampal and cortical cell cultures. minocycline blocked 3-NP-induced neurotoxicity at certain doses (1 mm cortical neurons) but not at higher doses (10 mm). Thus, minocycline may have variable and even deleterious effects in different species and models according to the mode of administration and dose.
Diguet
Elsa
E
Physiologie et Physiopathologie de la Signalization Cellulaire, UMR-CNRS 5543, Université Victor Segalen Bordeaux2, 146 rue Léo Saignat, 33076, Bordeaux, France.
Fernagut
Pierre-Olivier
PO
Wei
Xing
X
Du
Yansheng
Y
Rouland
Richard
R
Gross
Christian
C
Bezard
Erwan
E
Tison
François
F
D000818:Animals; D002478:Cells, Cultured; D003292:Convulsants / Q000633:toxicity; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D006816:Huntington Disease / Q000139:chemically induced / Q000188:drug therapy*; D007150:Immunohistochemistry; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008911:Minocycline / Q000009:adverse effects*; D009410:Nerve Degeneration / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000009:adverse effects*; D009574:Nitro Compounds; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D011422:Propionates / Q000633:toxicity
D003292:Convulsants; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D011422:Propionates; D008911:Minocycline; C015392:3-nitropropionic acid