The neuropathology in many neurodegenerative diseases is mediated by inflammatory cascades that influence neuronal dysfunction and death. Minocycline reduces the neurodegeneration observed in various models of Parkinson's. We exploited the unilateral 6-hydroxydopamine (6-OHDA) lesion model to assess the effect of minocycline on related neurodegeneration. Thirty Fisher 344 rats were divided into three daily treatment groups: (1) after: 45 mg/kg of minocycline beginning 24 h after lesioning; (2) before: 45 mg/kg of minocycline beginning 3 days before 6-OHDA lesioning; (3) control: corresponding saline-treated controls. Animals were assessed for apomorphine-induced rotations for 4 weeks. A longitudinal model for repeated measures showed that both after and before groups had significantly lower rotations than controls (P < 0.001 for both comparisons). Pair-wise group comparisons showed that the before animals rotated less compared to controls (mean rotations: 164 +/- 38 versus 386 +/- 49, respectively, P = 0.001). After animals also rotated significantly less then controls (mean rotations: 125 +/- 41 versus 386 +/- 49, respectively, P < 0.001). Animals receiving minocycline displayed reduced tyrosine hydroxylase-positive cell loss in the lesioned nigra versus contralateral nonlesioned nigra, compared to controls (mean differences: 5065 for after, 3550 for before, and 6483 for controls; P = 0.158 for after versus controls, P = 0.019 for before versus controls). The remaining lesioned nigral cells of both minocycline-treated groups were larger than controls, with the most robust cell size and fiber density observed in the after group. These data suggest that the therapeutic potential of minocycline may depend on the time of drug administration relative to neuropathogenic event.