Striatal trophic factor activity in aging monkeys with unilateral MPTP-induced parkinsonism.

Striatal trophic activity was assessed in female rhesus monkeys of advancing age rendered hemiparkinsonian by unilateral intracarotid administration of MPTP. Three age groups were analyzed: young adults (8-9.5 years) n=4, middle-aged adults (15-17 years) n=4, and aged adults (21-31 years) n=7. Fresh frozen tissue punches of caudate nucleus and putamen were collected 3 months after MPTP treatment and assayed for combined soluble striatal trophic activity, brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). This time point was chosen in an effort to assess a relatively stable phase of the dopamine (DA)-depleted state that may model the condition of Parkinson's disease (PD) patients at the time of therapeutic intervention. Analyses were conducted on striatal tissue both contralateral (aging effects) and ipsilateral to the DA-depleting lesion (lesion x aging effects). We found that combined striatal trophic activity in the contralateral hemisphere increased significantly with aging. Activity from both middle-aged and aged animals was significantly elevated as compared to young adults. Following DA depletion, young animals significantly increased combined striatal trophic activity, but middle-aged and aged animals did not exhibit further increases in activity over their elevated baselines. BDNF levels in the contralateral hemisphere were significantly reduced in aged animals as compared to young and middle-aged subjects. With DA depletion, BDNF levels declined in young and middle-aged animals but did not change from the decreased baseline level in old animals. GDNF levels were unchanged with aging and at 3 months after DA depletion. The results are consistent with several conclusions. First, by middle age combined striatal trophic activity is elevated, potentially reflecting a compensatory reaction to ongoing degenerative changes in substantia nigra DA neurons. Second, in response to DA depletion, young animals were capable of generating a significant increase in trophic activity that was sustained for at least 3 months. This capacity was either saturated or was not sustained in middle-aged and aged animals. Third, the aging-related chronic increase in combined striatal trophic activity was not attributable to BDNF or GDNF as these molecules either decreased or did not change with aging.