Comparison of the capability of GDNF, BDNF, or both, to protect nigrostriatal neurons in a rat model of Parkinson's disease

Abstract

Both glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) can protect nigrostriatal dopaminergic neurons from neurotoxins in rodent and monkey models of Parkinson's disease (PD). These two neurotrophic factors are usually tested individually. This study was designed to compare GDNF, BDNF, or both, for their capabilities to correct behavioral deficits and protect nigrostriatal dopaminergic neurons in a rat model of PD. Gene transfer used a helper virus-free Herpes Simplex Virus (HSV-1) vector system and a modified neurofilament heavy gene promoter that supports long-term expression in forebrain neurons. Rats received unilateral intrastriatal injections of HSV-1 vectors that express either GDNF or BDNF, or both vectors, followed by intrastriatal injections of 6-hydroxydopamine (6-OHDA). Recombinant GDNF or BDNF was detected in striatal neurons in rats sacrificed at 7 months after gene transfer. Of note, GDNF was significantly more effective than BDNF for both correcting behavioral deficits and protecting nigrostriatal dopaminergic neurons. Expression of both neurotrophic factors was no more effective than expression of only GDNF. These results suggest that GDNF is more effective than BDNF for correcting the rat model of PD, and that there are no detectable benefits from expressing both of these neurotrophic factors.

Evaluation and optimization of the administration of a selectively replicating herpes simplex viral vector to the brain by convection-enhanced delivery

“…16 Clearly this has the potential to make the effective intracranial administration of HSV-1-based vectors unachievable. Nevertheless, in addition to the aforementioned clinical trials, [6][7][8][9] HSV vectors have been administered by stereotactic injection into normal mouse, [17][18][19] rat [20][21][22][23][24][25][26] and primate brains, [20][21][22][23][24][25][26][27][28] animal models of high-grade glioma, [29][30][31][32][33][34][35] mucopolysaccharidosis type VII, 36 GM2 gangliosidosis 37 and Parkinson's disease, [37][38][39] as well as being administered by CED into a glioma rat model. 40 In view of there being this large number of studies, it is surprising that to date no attempt has been made to systematically evaluate and optimize the delivery of these vectors directly into the brain.…”

Shedding light into the role of BDNF in the pharmacotherapy of Parkinson's disease

“…A very recent manuscript showed that GDNF performed better than BDNF for protecting nigrostriatal dopaminergic neurons and correcting the related behavioral deficits caused by intrastriatal injections of 6-hydroxydopamine. 129 However, the capability to restore dopaminergic neurons was not additive or synergistic when the two neurotrophins were co-expressed. 129 This evidence is corroborated by Onyango et al 130 who demonstrated that BDNF and GDNF utilize distinct intracellular signaling pathways to protect cytoplasmic hybrid cells made from mitochondrial DNA of idiopathic PD individuals.…”

“…129 However, the capability to restore dopaminergic neurons was not additive or synergistic when the two neurotrophins were co-expressed. 129 This evidence is corroborated by Onyango et al 130 who demonstrated that BDNF and GDNF utilize distinct intracellular signaling pathways to protect cytoplasmic hybrid cells made from mitochondrial DNA of idiopathic PD individuals. These observations add to the complexity of the mechanisms responsible for the neurotrophin-mediated neuroprotection of dopaminergic neurons and further pinpoint to the selective modulation of endogenous trophic factors as a feasible option to correct specific deficits of the disease.…”

Alphavirus Vectors for Therapy of Neurological Disorders

“…Furthermore, AAV-based NGF therapy in a phase I clinical trial in 8 patients with mild Alzheimer's disease demonstrated no long-term adverse effects, suggested reduced rate of cognitive decline and increase in cortical 18-fluorodeoxyglucose based on PET scans [6]. Similarly, helper-free HSV-1 vectors expressing GDNF and BDNF were evaluated in a rat model for Parkinson's disease [7]. In rats sacrificed 7 months after intrastriatal HSV-1 administration, significantly superior benefits measured as correction of behavioral deficits and protection of nigrostriatal dopaminergic neurons were observed for GDNF in comparison to BDNF.…”