Int. J. Devl Neuroscience 21 (2003) 391–400 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 R.K. Chaturvedi a , A.K. Agrawal a,∗ , K. Seth a , S. Shukla a , S. Chauhan c , Y. Shukla b , C. Sinha a , P.K. Seth a a Developmental Toxicology Division, Industrial Toxicology Research Centre, P.O. Box 80, M.G. Marg, Lucknow 226 001, India b Environmental Carcinogenesis Division, ITRC, Lucknow, India c School of Studies in Botany, Jiwaji University, Gwalior, India Received 9 May 2003; received in revised form 4 June 2003; accepted 17 June 2003 Abstract Among trophic factors already known, glial cell line-derived neurotrophic factor (GDNF) and other members of its family have po- tent 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, neuro- chemical 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. © 2003 ISDN. Published by Elsevier Ltd. All rights reserved. Keywords: d-Amphetamine; Dopamine; Caudate putamen; Tyrosine hydroxylase; GDNF 1. Introduction Parkinson’s disease (PD), is a progressive neurodegen- erative disorder, characterized by the loss of nigrostriatal dopaminergic neurons (Jellinger, 1987). Levodopa, a pre- cursor of dopamine (DA) has been considered major thera- peutic drug, however, l-dopa slowly becomes less effective after long term treatment and shows undesirable side effects (Fahn, 1996). In last decades neural transplantation of fetal dopaminergic tissue into the denervated striatum has been considered as an approach to replenish striatal dopamine ∗ Corresponding author. Tel.: +91-522-2213618; fax: +91-522-2228227. E-mail address: aka33@rediffmail.com (A.K. Agrawal). level and to reform the nigrostriatal pathway (Bjorklund, 1992; Mendez et al., 1992; Nikkhah et al., 1995). However limits of donor fetal tissue at the time of transplantation, poor cell survival (∼5–10%) (Kordower, 1998) and lim- ited host reinnervation are the major shortcomings of this approach. Although the reasons for the poor survival of transplant are yet to be established, it is likely that poor cell survival owe to many factors such as mismatch condi- tions, lack of trophic support, free radical mediated toxicity (Jenner, 1994) and apoptosis (Zawada, 1998). Attempts have been made to improve the survival of grafted ni- gral neurons using neurotrophic factors (Johansson et al., 1995; Mayer et al., 1993; Rosenblad et al., 1996; Sinclair et al., 1996; Takayama et al., 1995; Yurek et al., 1996), antioxidants (Dugan et al., 2001; Nakao et al., 1994) and 0736-5748/$30.00 © 2003 ISDN. Published by Elsevier Ltd. All rights reserved. doi:10.1016/S0736-5748(03)00087-X