Intracerebral Drug Infusion Glial Cell Line Derived Neurotrophic Factor

The Parkinson's-Reversing Breakthrough

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Glial cell line-derived neurotrophic factor (GDNF) was first identified in the early 1990s as a member of the transforming growth factor (TGF)-beta superfamily with potent effects on embryonic neuronal cultures and specifically on dopaminergic cell lines (29). It was subsequently found to be potently expressed in the developing rodent striatum (30). Its potential as a possible agent for the protection of dopamin-ergic projections was quickly recognized and there was investigation into the delivery of the agent in animal PD models.

Early studies showed that local GDNF administration was able to protect and restore dopaminergic cells in rodent models of PD (31,32). Shortly thereafter, trials in primates confirmed the ability of GDNF both to protect dopaminergic cells from degeneration and to improve functional assessments of motor behavior in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus monkeys (33,34). The success of these studies generated hope for the clinical utility of GDNF in patients with PD (35,36). Anecdotal reports, however, were mixed, with some indicating improvement (37) and others indicating treatment futility (38). Overall, there were few publications from which conclusions could be drawn. However, the preclinical evidence was sufficiently compelling to spur broader investigation.

The first, large, randomized trial of intraventricular GDNF was published in 2003. In this trial, 50 patients underwent placement of pumps and intraventricular catheters. The patients were randomized to receive either carrier alone or one of several concentrations of recombinant GDNF. At six to eight months, none of the GDNF groups had demonstrated improvements over placebo and several of the groups had worsened (39). Additionally, adverse effects were noted in 100% of patients receiving GDNF. These included nausea, anorexia, and shock-like sensory symptoms resembling Lhermitte's phenomena. It was suggested that the relative size of the human brain makes the transependymal diffusion of GDNF insufficient to create the necessary concentrations to produce an effect (40).

A series of trials were also underway to evaluate the effects of intrastriatal microinfusion of GDNF. A phase I safety study published by Gill et al. reported that microinfusion in five parkinsonian patients produced no significant adverse effects and improved UPDRS scores by 48%. Furthermore, positron emission tomography (PET) scanning demonstrated increased striatal dopamine uptake (40). Notable side effects also included anorexia, with significant weight loss, and Lhermitte's phenomenon. The results of this study were sufficient to begin a phase II study with a randomized blinded design for the striatal administration of GDNF or carrier. This study included 34 patients who underwent implantation of intraputaminal catheters and pumps and then received either GDNF or saline carrier alone. At six months, the GDNF-treated patients failed to show significant changes in their off-medication UPDRS motor scores compared with placebo. Although there was a trend for more severely affected patients to derive improvement, this did not meet significance. Additionally, four of the patients developed anti-GDNF antibodies during or subsequent to the six-month period of study, raising concerns that autoimmune consequences might ensue (41). Despite the failure of clinical response in this study, PET imaging performed in treated patients demonstrated an average 23.1% increase in F-dopa uptake compared to a decrease of 8.8% in placebo-treated patients (41). This objective sign of treatment effect and the benefits demonstrated in previous open-label studies raise the possibility that GDNF treatment may still hold promise. Current hopes rest on cell- and viral-based gene therapy treatments.

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Breaking Bulimia

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We have all been there: turning to the refrigerator if feeling lonely or bored or indulging in seconds or thirds if strained. But if you suffer from bulimia, the from time to time urge to overeat is more like an obsession.

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