Restorative Effects of Platelet Derived Growth Factor-BB in Rodent Models of Parkinson's Disease

Abstract

Parkinson's disease is characterized by motor deficits caused by loss of midbrain dopaminergic neurons. Neurotrophic factors and cell transplantation have partially restored function in models of Parkinson's disease, but have had limited effects in humans. Here we show that intracerebroventricular administration of platelet-derived growth factor-BB can offer an alternative strategy to restore function in Parkinson's disease; In animal models of nigrostriatal injury, a two weeks treatment with plateletderived growth factor-BB resulted in long-lasting restoration of striatal dopamine transporter binding sites and expression of nigral tyrosine hydroxylase. It also normalized amphetamine-induced rotational behavior in 6-hydroxydopamine lesioned rats. Platelet-derived growth factor-BB promoted proliferation of neural progenitor cells in the subventricular zone. The effects on dopaminergic neurons and functional recovery could be blocked by co-infusion with a proliferation inhibitor, indicating a link between the proliferative and anti-parkinsonian effects. Based on the current data, we consider platelet-derived growth factor-BB a clinical candidate drug for treatment of Parkinson's disease.

Neurogenesis in the Striatum of the Adult Human Brain

“…Increasing the generation or promoting the survival of new neurons is an interesting option in stroke. Moreover, studies in rodents have suggested that promoting cell proliferation in the subventricular zone can have a positive effect in models of Parkinson's disease, likely mediated by the new cells having a neurotrophic effect on the nigro-striatal system (Androutsellis-Theotokis et al, 2009;Zachrisson et al, 2011). Investigating how striatal neurogenesis is potentially affected in pathological situations and identifying factors that promote the renewal of striatal neurons may facilitate the development of therapeutic strategies to improve functional recovery after injury or to tackle neurodegenerative disorders.…”

Current disease modifying approaches to treat Parkinson’s disease

“…PDGF-BB was also increased in brain after treatment with 6-OHDA suggesting a compensatory response [98]. Along this line, PDGF-BB injections induced functional recovery and provided neuroprotection of the lesioned nigrastriatal system [99]. Data showed that PDGF-BB might act not directly on dopaminergic neurons, but on neural progenitor and stem cells in the subventricular zone to enhance neurogenesis [99].…”

“…Along this line, PDGF-BB injections induced functional recovery and provided neuroprotection of the lesioned nigrastriatal system [99]. Data showed that PDGF-BB might act not directly on dopaminergic neurons, but on neural progenitor and stem cells in the subventricular zone to enhance neurogenesis [99]. Together these results raised the possibility that stimulation of neurogenesis in the brain can enhance recovery and possibly halt the process of cell degeneration in PD.…”

Chondroitinase ABC reduces dopaminergic nigral cell death and striatal terminal loss in a 6-hydroxydopamine partial lesion mouse model of Parkinson’s disease

“…However, digestion of the CS-GAGs is believed to liberate ligands such as various growth factors that aid plasticity [23][24][25]. Given that several growth factors are known to enhance survival of dopaminergic neurones, such as glial-derived neurotrophic factor, cerebral dopaminergic neurotrophic factor, platelet-derived growth factor-BB and fibroblast growth factor 20 [26][27][28][29][30], the liberation of these growth factors following digestion could certainly explain the protective effects seen here. Further studies will be required to establish the underlying mechanisms.…”