Effect of glial cell line‐derived neurotrophic factor (GDNF) co‐transplantation with fetal ventral mesencephalic cells (VMC) on functional restoration in 6‐hydroxydopamine (6‐OHDA) lesioned rat model of Parkinson's disease: neurobehavioral, neurochemical and immunohistochemical studies

Abstract

Among trophic factors already known, glial cell line-derived neurotrophic factor (GDNF) and other members of its family have potent and specific action on dopaminergic neurons. In the present investigation an attempt has been made to validate the role of GDNF co-transplantation with fetal ventral mesencephalic cells (VMC) on functional viability and restoration using neurobehavioral, neurochemical and immunohistochemical parameters at 6 weeks post-transplantation in 6-hydroxydopamine (6-OHDA) lesioned rat model of Parkinson's disease (PD). A significant restoration (P<0.01) in D-amphetamine induced rotations, spontaneous and apomorphine induced locomotor activity in rats co-transplanted with VMC and GDNF was observed as compared to VMC alone transplanted rats. Level of dopamine (DA), 3,4-dihydroxy-phenyl acetic acid (DOPAC) and dopamine D2 (DA-D2) receptors in the caudate putamen (CPu) were significantly (P<0.001) restored in co-transplanted group as compared to VMC transplanted or GDNF administered animals. The functional viability of transplanted VMC was confirmed by tyrosine hydroxylase (TH) expression and quantification of TH-positive cells by image analysis revealed a significant restoration in TH-IR fibers density as well as TH-IR neurons counts in co-transplanted animals over VMC transplanted animals. Results suggest that co-transplantation of VMC and GDNF may be a better approach towards functional restoration in 6-OHDA lesioned rat model of Parkinson's disease.

How to improve the survival of the fetal ventral mesencephalic cell transplanted in Parkinson’s disease?

“…It is well documented that GDNF can reduce dopaminergic neurons apoptosis, increase the survival and differentiation of fetal dopaminergic cell in vitro [17] . It has also been shown that GDNF can increase dopaminergic cell survival, graft-derived fiber outgrowth and overall functions of the graft after neural transplantation in rodent model of PD [18] . But the effect depends on the juncture and the dose of the GDNF addition.…”

Restorative potential of dopaminergic grafts in presence of antioxidants in rat model of Parkinson's disease

“…DA and DOPAC levels in cultures were measured according to the modified method of Chaturvedi et al (2003). In brief, cultures were harvested by repeated pipetting and with the help of cell scraper.…”

“…Twelve weeks post transplantation six rats from each group (sham, lesioned, all transplanted groups) were assessed for circling behavior after injecting 5 mg/kg Damphetamine i.p following the method of Chaturvedi et al (2003). Rotational behavior was recorded after 30 min of injection, assessed for a period of 30 min and expressed as number of rotations/30 min.…”

“…The brains were removed quickly and the caudate putamen region of striatum was dissected in cold condition. The levels of DA and its metabolite DOPAC were measured in the striatal region and in cultured VMC following the method of Chaturvedi et al (2003), by high-performance liquid chromatography (HPLC), using electrochemical detector (Merck, L-3500 A). The separation of DA and DOPAC was obtained, using mobile phase containing 10% methanol, 32 mM citric acid, 12.5 mM Na 2 HPO 4 , 0.5 mM octyl sodium sulphate and 0.05 mM EDTA.…”

“…Poor survival of grafted cells may be attributed to many factors such as free radical mediated toxicity, lack of trophic factor support and apoptosis (Zawada et al, 1998). Different strategies have been worked out to promote survival of transplanted fetal cells through trophic factor support (Yurek et al, 1996;Chaturvedi et al, 2003), multiple microtransplantation approach (Nikkhah et al, 1994), antioxidants (Dugan et al, 2001) and antiapoptotic agents (Schierle et al, 1999). Although various mechanisms contribute towards loss of transplanted dopaminergic neurons during early post transplantation period, however, there is an increasing evidence that free radical mediated factors play an important role in death of transplanted cells (Nakao et al, 1994).…”