Chronic, controlled GDNF infusion promotes structural and functional recovery in advanced parkinsonian monkeys

Abstract

The powerful trophic effects that glial cell line-derived neurotrophic factor (GDNF) exerts on midbrain dopamine neurones suggest its use in treating Parkinson's disease. However, some important questions remain about the possible therapeutic applications of GDNF. Here we demonstrate that the chronic infusion of 5 or 15 micro g/day GDNF into the lateral ventricle or the striatum, using programmable pumps, promotes restoration of the nigrostriatal dopaminergic system and significantly improves motor functions in rhesus monkeys with neural deficits modelling the terminal stages of Parkinson's disease. The functional improvements were associated with pronounced upregulation and regeneration of nigral dopamine neurones and their processes innervating the striatum. When compared with vehicle recipients, these functional improvements were associated with (i) >30% bilateral increase in nigral dopamine neurone cell size; (ii) >20% bilateral increase in the number of nigral cells expressing the dopamine marker tyrosine hydroxylase; (iii) >70 and >50% bilateral increase in dopamine metabolite levels in the striatum and the pallidum, respectively; (iv) 233 and 155% increase in dopamine levels in the periventricular striatal region and the globus pallidus, respectively, on the lesioned side; and (v) a five-fold increase in tyrosine hydroxylase-positive fibre density in the periventricular striatal region on the lesioned side. In addition, chronic GDNF treatment did not induce the side-effects generally associated with chronic administration of levodopa, the most widely used treatment for Parkinson's disease. Thus, the results suggest that the prolonged and controlled delivery of GDNF into the brain could be used to intervene in long-term neurodegenerative disease processes like Parkinson's disease. Additional studies are required to determine the potential differences between chronic, intraventricular and intraputamenal (or intranigral) delivery of GDNF to maximize the efficacy of infusion treatments.

Neurotrophic factors for the treatment of Parkinson's disease

“…while intraventricular injections of GDNF were found to increase intrastriatal but not intranigral dopamine levels [43]. Infusion of GDNF into the putamen of MPTP-treated monkeys induced a gradual and significant reduction in parkinsonian symptoms [44]. This appeared to be a regenerative action, since GDNF was injected at three months after the MPTP lesion, when the nigrostriatal pathway had presumably undergone significant degeneration.…”

Treatment of Parkinson’s Disease with Trophic Factors

“…[37][38][39] Unlike the case with BDNF, however, there is also evidence for restoration of function of injured neurons by GDNF after toxic insults 33,36,40 although restorative actions are generally not as dramatic as the neuroprotective actions. 33 A series of influential studies from Gash, Gerhardt, and coworkers [41][42][43] have demonstrated GDNF-induced improvement in bradykinesia, rigidity, and postural instability in monkeys with stable MPTP-induced hemiparkinsonism. GDNF was effective when given by bolus or by constant infusion, and through three routes of administration: intranigral, intrastriatal, and intracerebroventricular (ICV).…”

Globus pallidus plays a critical role in neurotrophic factor induced functional improvements in hemiparkinsonian monkeys

“…Procedures were described previously (3,7). For the nigral DA levels in the animals with pallidal lesins, 10 tissue punches from the right SN (ipsilateral to the MPTP administration and the pallidal lesion) from each monkey were obtained from the 4 mm thick coronal section throught the SN as previous described (14).…”

“…Studies from our group have consistently demonstrated that intracerebral administration of GDNF could not only significantly improve overall parkinsonian features, but also increase levels of dopamine (DA) and homovanillic acid (HVA), a metabolite of dopamine, especially in the pallidal regions in which the changes of DA and HVA in the GP were even more robust than what were observed in the caudate and putamen in normal (3), aged (4) and parkinsonian monkeys (5,6,7). For example, in the aged animals (4), robust increases of DA were found in the globus pallidus by 390% (P<0.01) on the GDNF-treated hemisphere compared with 50% (P<0.05) in the caudate nucleus, while the increase of DA failed to reach significance in the putamen following GDNF administration.…”