Figure 1.
Blocking TNF signaling in the nigra attenuates striatal 6-OHDA-induced loss of nigral DA neurons and drug-induced rotational behavior. A unilateral striatal lesion was induced by injecting 6-OHDA (20 μg) into the CPu complex of young adult rats; mock-lesioned animals received an injection of saline. Animals were stereotaxically implanted with an ipsilateral striatal or nigral indwelling cannula connected to an Alzet 2002 osmotic pump to deliver saline vehicle or XENP345 (0.08 mg · kg−1 · d−1) over a 2 week period. Animals were anesthetized, and brains were fixed for immunohistochemical analyses of TH/NeuN-IR neurons by intracardiac perfusion 3 weeks after the lesion. Panels from top to bottom represent increasing magnification of representative brain sections used to obtain stereological estimates of nigral DA neuron number in 6-OHDA-lesioned animals implanted with pump preloaded with saline [contralateral unlesioned side (a); lesioned/pump side (b)] or implanted with nigral pump preloaded with XENP345 [contralateral unlesioned side (c); lesioned/pump side (d)]. Scale bar: top panel, 100 μm; middle panel, 50 μm; bottom panel, 10 μm. e, Stereological estimate of DA neuron number (TH/NeuN-IR cells) in SNpc expressed as a percentage of the contralateral side (solid bars). Statistical significance was evaluated by ANOVA followed by post hoc comparison test between groups and to unlesioned control group. Values expressed are group mean + SEM; *p < 0.05; **p < 0.01; ***p < 0.001. Fluorescence intensity of TH-immunoreactive fibers was used to estimate striatal TH-fiber density (hatched bars) on the lesioned side, expressed as a percentage of the unlesioned contralateral side. f, As a physiological measure of striatal DA depletion in mock- or 6-OHDA-lesioned animals, rotational behavior induced by an intraperitoneal injection of 2.5 mg/kg amphetamine was measured weekly in all animals and expressed as the number of ipsilateral turns per minute. Values expressed are group mean ± SEM; **p < 0.01.