Objective: To evaluate overexpression of the neuroprotective vascular endothelial growth factor B (VEGF-B) in a genetic Parkinson’s disease (PD) model.

Background: We have shown in prior work that VEGF-B is neuroprotective in toxin-induced (rotenone; 6-OHDA) rat models in vitro and in vivo (Yue et al., 2014). Here, we further assess the neuroprotective effects of VEGF-B using a PTEN-induced putative kinase 1 (PINK1) knockout (KO) rat model, a novel genetic PD model. Mutations in the PINK1 gene have been shown to be a cause of human familial PD cases. PINK1 KO rats gradually develop motor impairment, evident at 7-8 month of age, and 50% dopaminergic cell loss in the substantia nigra (SN) at 8 months, reflecting a slow and progressive degeneration.

Methods: In a preliminary study (n=5-6), at 5 months of age PINK1 KO rats were injected unilaterally with an adeno-associated virus expressing human VEGF-B (AAV2/1-CAG-hVEGF-B) into two sites in the striatum (AP +1.0, ML +3.0, DV −5.0 and AP −0.6, ML +3.5, DV −5.0) and one in the SN (AP −5.0, ML −2.0, DV −7.2). Behavioral analyses were compared to PINK1 KO rats and Wild-Type Long-Evans controls. Changes in motor function were tracked monthly using an array of behavioral tests, including forelimb adjusting steps to evaluate forepaw function, as well as the tapered balance beam to evaluate hindlimb function. At 13 months the animals were sacrificed, striatal protein was isolated and striatal dopamine (DA) levels were measured with HPLC-EC.

Results: Our data show behavioral deficits in PINK1 KO rats reach maximum level at 8-months. Further aging does not increase deficits, indicating its utility as an early PD model. An increase in bilateral hindlimb slips is evident in PINK1 KO rats at 7-10 months. PINK1 KO rats show strong trends of improved motor behavior after unilateral VEGF-B over-expression in SN and striatum, not reaching significance in our small pilot study. We quantified striatal DA content and are currently testing for the integrity of the dopaminergic system, by analyzing tyrosine hydroxylase content in the SN and striatum. Striatal DA levels were reduced by 20-30% in PINK1 KO rats compared to WT, but in the AAV2/1-CAG-hVEGF-B injected hemisphere DA was restored close to WT level (n=3-5).

Conclusions: Our pilot data indicate that VEGF-B overexpression might have a neuroprotective effect in PINK1 KO rats.

References: Yue X, Hariri DJ, Caballero B, Zhang S, Bartlett MJ, Kaut O, Mount DW, Wüllner U, Sherman SJ, Falk T; Comparative study of neurotrophic effects by VEGF-B and GDNF in preclinical in vivo models of Parkinson’s disease. Neuroscience 2014; 258:385-400.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/aav-mediated-over-expression-of-vegf-b-in-pink1-gene-knockout-rats-increases-striatal-dopamine-content/