Table 1.

Pharmacological modulation of proteasome inhibitor-induced striatal DA and TH cell loss

	Striatal DA levels (% of control) DLS	TH-positive nigral cells (% of control)
Treatment	Striatal DA levels (% of control) DLS	Dorsal tier	Ventral tier
Lactacystin	32.2 ± 6.0^*	61.4 ± 7.0^*	23.1 ± 2.8^*
Epoxomycin	40.9 ± 6.3^*	55.1 ± 4.9^*	28.2 ± 2.9^*
l-DOPA	113.6 ± 8	105.4 ± 7.9	96.1 ± 8.5
α-MpT	95.2 ± 6.8	98.5 ± 9.3	107.8 ± 6.3
Pargyline	102.5 ± 1.7	92.9 ± 6.5	91.4 ± 4.6
Lactacystin plus α-MpT	85.2 ± 11^**	88.4 ± 6.5^**	83.7 ± 7.2^**
Epoxomycin plus α-MpT	93.1 ± 12.5^**	77.6 ± 7.2^**	78.2 ± 7.9^**
Lactacystin plus l-DOPA	15.9 ± 2.8^**	41.7 ± 5.8^**	12.1 ± 1.1^**
Epoxomycin plus l-DOPA	29.6 ± 3.0^**	27.1 ± 3.5	14.2 ± 2.2^*
Lactacystin plus pargyline	26.0 ± 3.5^**	52.1 ± 4.8	12.5 ± 2.4^**
Epoxomycin plus pargyline	28.6 ± 2.1^**	33.1 ± 4.5	15.7 ± 3.2^**

Striatal effects were measured from the DLS microinfused with epoxomycin-lactacystin (Fig. 1a) or the controlateral DLS microinfused with saline (controls). Striatal DA levels were obtained from striatal homogenates of DLS. Nigral effects were measured on 20-μm-thick sections from 10 serial slides of substantia nigra along the rostrocaudal exent shown in Figure 1b. TH-Immunostained cells were counted from eight rats per group from the nigra ipsilateral to the microinfused striatum, and the contralateral nigra (ipsilateral to the striatum microinfused with saline) served as control. We found that intrastriatal infusion of proteasome inhibitors produced a significant loss of striatal DA levels and ipsilateral retrograde loss of nigral TH-immunostained cells. This effect was more pronounced in the ventral compared with the dorsal part of the substantia nigra. Lactacystin and epoxomycin were infused at the concentration of 100 μm on the basis of the dose-response experiments reported in Results. l-DOPA was administered as methyl-l-DOPA hydrochloride (100 mg/kg, free base), α-MpT was microinfused at the dose of 150 mg/kg, and pargyline was injected at the dose of 75 mg/kg. These compounds had no effects when injected alone; however, α-MpT prevented and both l-DOPA and pargyline worsened the deleterious effects produced by proteasome inhibition. Values are expressed as percentage of controls. ^*p < 0.05 compared with controls. ^**p < 0.05 compared with lactacystin or epoxomycin alone.