Subthalamic nucleus lesions are neuroprotective against terminal 6-OHDA-induced striatal lesions and restore postural balancing reactions

Inactivation of the subthalamic nucleus (STN) by deep brain stimulation or lesioning can ameliorate symptoms in Parkinson' disease (PD) and may alter the underlying progressive degenerative process. We evaluated the effects of STN lesions in a terminal lesion model of PD in rats. Multiple intrastriatal 6-OHDA injections (4 x 7 microg) resulted in a partial loss of striatal TH-positive innervation (-30 to -40%) and nigral dopaminergic neurons (-60%), which was associated with behavioral deficits as observed in drug-induced rotational asymmetry, side-stepping, and postural balancing reactions. Unilateral ibotenic acid lesions of the STN did produce a 50-60% loss of STN neurons based on stereological analysis, which did not induce a functional impairment in rotational asymmetry or spontaneous sensorimotor behaviors. When STN lesions were performed 1 week prior to the 6-OHDA terminal striatal lesions, a significant rescue effect (+23%) on nigral dopaminergic neurons against terminal 6-OHDA neurotoxicity could be demonstrated, whereas striatal TH-positive fiber loss was not attenuated in these animals. In addition, animals with combined STN and striatal lesions exhibited a significant recovery in postural balancing reactions induced by 6-OHDA terminal lesions and did not show a significant impairment in any of the other behavioral parameters examined. Taken together, STN lesions can exert neuroprotective effects on nigral dopamine neurons in a partial lesion model of PD which result in recovery of spontaneous sensorimotor behavior. These findings may therefore provide new insights into the functional interaction between the glutamatergic and the dopaminergic neurotransmitter systems and foster novel therapeutic concepts for the early and middle phases of Parkinson's disease.