Glial cell line-derived neurotrophic factor (GDNF): a drug candidate for the treatment of Parkinson’s disease

Abstract

Considerable effort has been devoted to the search for molecules that might exert trophic influences on midbrain dopamine neurons, and potentially be of therapeutic value in the treatment of Parkinson's disease. One such candidate is glial cell line-derived neurotrophic factor (GDNF). GNDF is distantly related to the transforming growth factor-beta superfamily and is widely expressed in many neuronal and non-neuronal tissues. GDNF uses a multisubunit receptor system in which GFRalpha-1 and Ret function as the ligand-binding and signalling components, respectively. In addition to its effects on cultured fetal midbrain dopamine neurons, GDNF promotes recovery of the injured nigrostriatal dopamine system and improves motor functions in rodent and nonhuman primate models of Parkinson's disease. Intraventricular, intrastriatal and intranigral routes of administration are efficacious in both models. In parkinsonian nonhuman primates, GDNF treatment improves bradykinesia, rigidity and postural instability. In this model, adult midbrain dopamine neurons stimulated by GDNF show increased cell size, neuritic extent, and expression of phenotypic markers. The neurorestorative effects of a single administration of GDNF last for at least a month and can be maintained in rhesus monkeys by monthly injections. GDNF also induces neuroprotective changes in dopamine neurons, which are active within hours following trophic factor administration in rodents. The powerful neuroprotective and neurorestorative properties of GDNF seen in preclinical studies suggest that trophic factors may play an important role in treating Parkinson's disease.

Effective GDNF brain delivery using microspheres—A promising strategy for Parkinson's disease

“…The trophic effect of GDNF on the dopaminergic system is widely acknowledged in the current bibliography [1,2]. However, the potential value of this protein for PD treatment is hindered by several safety and efficacy concerns related to the brain delivery strategies attempted so far.…”

“…Among them, the glial cell-line derived neurotrophic factor (GDNF) was selected as the most suitable candidate for the treatment of Parkinson´s disease (PD) due to its strong trophic effect on the dopaminergic system [1,2]. The initial successful results obtained in relevant animal models of the disease led to different clinical trials in PD patients.…”

Gdnf signaling pathways within the mammalian spermatogonial stem cell niche

“…Gdnf also promotes the differentiation of several types of peripheral neurons (Zurn et al, 1996). Because it improves motor functions in animal models of parkinsonism, Gdnf has been seen as a promising therapy for Parkinson disease (Grondin and Gash, 1998). The role of Gdnf in embryonic development is not limited to the nervous system and it is also essential for kidney and gastrointestinal tract formation (Schuchardt et al, 1994;Moore et al, 1996;Hellmich et al, 1996).…”

The identification of candidate genes and SNP markers for classical bovine spongiform encephalopathy susceptibility

“…GDNF has been shown to mitigate neuronal degeneration in a range of neurodegenerative conditions and was one of the first investigated targets for gene therapy in Parkinson disease. 36,37 GDNF is thought to promote survival and differentiation of developing neurons and to protect mature neurons. 36 Mutations in or impairments of GDNF action have been shown contribute to the symptoms of Down syndrome and Schizophrenia.…”