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...O'Malley, 2013). In rodent models of PD, it was shown that the axonal trees of the remaining axons can re-innervate the striatal areas left vacant by the degenerating dopaminergic neurons (Burke and O'Malley, 2013; Parish et al., 2001), opening an opportunity to halt or reverse the progression of PD via GDNF delivery. 2.2. Ectopic GDNF application for PD therapy Intracranial delivery of GDNF potentiates striatal dopamine system function and midbrain dopaminergic neuronal survival in several models of chemically-induced PD in rodents (Beck et al., 1995; Hoffer et al., 1994; Tomac et al., 1995; Winkler et al., 1996) as well as nonhuman primates (Gash et al., 1996). Interestingly, GDNF delivery into the striatum, but not to the SNpc, results in functional recovery in rodent PD models (Kirik et al., 2000, 2004), underlying the importance of GDNF delivery to its physiological site of expression for the treatment of PD. Upon intracranial delivery, GDNF induces re-growth of degenerating dopaminergic axons in PD animal models (Meissner et al., 2011) and in aging human brain (Love et al., 2005). In clinical trials, however, the effects of intracranial GDNF delivery varied from positive clinical benefits (Gill e...

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...ither the striatum or substantia nigra, intranigral injection of GDNF had protective effects on rat nigral dopaminergic cell bodies (Kearns & Gash, 1995). A series of four intrastriatal injections of GDNF was found to decrease drug-induced rotations and preserve nigrostriatal dopaminergic neurones in adult rats with 6-OHDAinduced striatal lesions (Shults et al., 1996). Long-term rescue of nigrostriatal dopaminergic neurones from intrastriatal 6-OHDA lesions was reported after short-term GDNF treatment, beginning five days after the lesion and being administered every fourth day for one month (Winkler et al., 1996). Long-term protection against rotational asymmetry, reductions in striatal dopamine levels and uptake, and death of nigral dopaminergic cell bodies induced by 6-OHDA lesions of the MFB was conferred by a single dose of GDNF, divided between the lateral ventricle and substantia nigra (Sullivan et al., 1998). GDNF injections into the striatum at one week after an intrastriatal 6-OHDA lesion resulted in reinnervation of the striatum as well as recovery of motor function (Rosenblad et al., 1998), indicating that the ability of intrastriatal GDNF injection to confer behavioural improvements may be...

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... growth factors prevent nigral cell loss and promote functional recovery (Spina, et al., 1992, Frim, et al., 1993, Lin, et al., 1993, Hyman, et al., 1994, Gash, et al., 1996, Kotzbauer, et al., 1996, =-=Winkler, et al., 1996-=-, Connor, et al., 1999, Bjorklund, et al., 2000, Kordower, et al., 2000). Based on these types of findings, a clinical trial of ICV GDNF protein infusion was performed in PD (Nutt, 2003). However, the...

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...ous reports on the effects of exercise on trophic factors in the striatum, each of these factors has potent trophic activity towards DA neurons (Hyman et al. 1991; Altar et al. 1992; Lin et al. 1993; =-=Winkler et al. 1996-=-) and, where examined, has been shown to protect against the neurotoxic effects of 6-OHDA (Hoffer et al. 1994; Kearns and Gash 1995; Levivier et al. 1995; Choi-Lundberg et al. 1998; Akerud et al. 1999...

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...5 or 7 days after lesion (when the terminal degeneration is ongoing but prior to DA cell death) produced protection of TH + neurons, though less complete protection of FG + cells (Sauer et al., 1995; =-=Winkler et al., 1996-=-). In contrast to our observations with V-10,367, Winkler et al. (1996) did not observe protection of striatal DA innervation or sprouting into the lesioned area, and no effects on amphetamineinduced ...

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...ate DA turnover and function. However when administered after 6-OHDA, GDNF is unable to provide the same neuroprotective effects, with a significant DA denervation still occurring within the striatum =-=[28,29]-=-. We therefore administered activin A for a full 7 days, beginning the day prior to injection of 6-OHDA, and quantified the number of remaining TH and NeuN positive cells 3 weeks after 6-OHDA administ...

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...igral injection of 100 µg of recombinant human GDNF reduced the rotations by ∼4-fold (Hoffer et al., 1994). Similar rescue effects of GDNF were reported in an independent study on the same rat model (=-=Winkler et al., 1996-=-). In 1995, four articles described the potent neurotrophic effects of GDNF on mesencephalic DA (Beck et al., 1995; Tomac et al., 1995a) as well as motor (Oppenheim et al., 1995; Yan et al., 1995) neu...

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...in rotational behaviour versus forelimb use may reflect differences in the neural control of these two responses. Indeed, forelimb use is dependent on a dopaminergic activity in the lateral striatum (=-=Winkler et al., 1996-=-; Chang et al., 1999; Tillerson et al., 2001; Lane et al., 2006), whereas a dopaminergic stimulation restricted to the substantia nigra may be sufficient to elicit rotation or locomotor activity (Robe...

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...4). The incapability of GDNF to cross the blood-brain-barrier requiressdirect administration of the factor into the brain. This can be accomplished by (i) directsinjection of the recombinant protein (=-=Winkler et al., 1996-=-; Lapchak et al., 1997; Kirikset al., 2000a; Rosenblad et al., 2000b), (ii) in vivo GDNF gene delivery using viralsvectors (Choi-Lundberg et al., 1997; Mandel et al., 1997; Bohn et al., 1999; Kirik et...