Infusion Therapy for Movement Disorders


Review of the Current Knowledge Base of the Topic

Direct intracerebral infusion of neurotrophic factors may represent a neuroprotective and neurorestorative therapeutic strategy for neurodegenerative movement disorders, most notably Parkinson’s disease (PD). A number of neurotrophins, including glial cell-line-derived neurotrophic factor (GDNF), neurteurin (NTN), cerebral dopamine neurotrophic factor (CDNF), and mesencephalic astrocyte-derived neurotrophic factor (MANF), are currently under preclinical and clinical investigation as infusional therapies for PD.

Infusion therapy has particular relevance to the treatment of PD, a common, debilitating, and incurable neurodegenerative disorder, because of a readily apparent “surgical target.” However, this strategy may also have application for the treatment of less common movement disorders, such as Huntington’s disease.

This chapter focuses on the preclinical and clinical evidence for the use of each of these four neurotrophins for the treatment of PD.

GDNF and NTN

GDNF and NTN are GDNF-family ligands, part of the transforming growth factor-β superfamily, a collection of multifunctional cytokines. Both neurotrophins have neuroprotective and neurorestorative effects in preclinical models of PD, leading to a number of early-phase clinical trials.

Preclinical Studies of GDNF and NTN Delivery for PD

The neuroprotective and neurorestorative effects of GDNF and NTN have largely been assessed in two validated preclinical models of PD: the 6-OHDA (6-hydroxydopamine) rodent model, and the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) nonhuman primate (NHP) model.

Intraventricular Administration of GDNF and NTN in Rodents

Infusion of recombinant human GDNF and 125 iodine-labeled GDNF ( 125 I-GDNF) into the ventricular system of nonlesioned rats resulted in diffusion of GDNF into superficial and deep brain structures, including the cerebral cortex, septum, diagonal band of Broca, fimbria, striatum, hippocampus, hypothalamus, substantia nigra (SN), ventral tegmental area, and cerebellum. Immunohistochemical staining revealed significantly increased levels of dopamine in both the striatum and SN.

In a head-to-head comparison of intraventricular infusion of GDNF and NTN, NTN proved ineffective in providing neuroprotection or neurorestoration, which the authors consider may have been due to its poor solubility and diffusivity. The same study confirmed the protective and restorative effects of intraventricular GDNF.

However, intraventricular infusion of GDNF was also found to produce increased hypothalamic dopamine content, resulting in significant cachexia in experimental animals. Intraventricular infusion of GDNF in 6-OHDA-lesioned rats resulted in locomotor improvements and increased striatal dopamine turnover. Reduced weight gain remained a consistent adverse effect. The small volume of the rodent brain and proximity of structures to the ventricular system led to studies in NHPs.

Intraventricular Administration of GDNF and NTN in Nonhuman Primates

Intraventricular infusion of GDNF in MPTP-lesioned rhesus monkeys and marmosets has been associated with mixed results. Significant improvements in locomotor activity were demonstrated following four monthly infusions at doses ranging from 100 to 1000 μg of GDNF, which were correlated with increases in dopamine metabolite concentrations in the SN but not the putamen. Improvements in locomotor function and reductions in l -dopa-induced dyskinesia have also been observed in marmosets receiving intraventricular GDNF infusions.

Comparable success was demonstrated in an NHP study of intraventricular infusion of NTN 48 h prior to MPTP exposure. Compared to control, animals receiving NTN demonstrated significant neuroprotective effects, with some NHPs developing no locomotor evidence of Parkinsonism at all. The authors concluded that intraventricular NTN could protect dopaminergic neurons from degeneration, preventing the onset of Parkinsonian symptoms.

However, the limited translational potential of intraventricular infusion was brought into sharp focus by an autoradiographic study of the distribution of 125 I-GDNF infused into the lateral ventricle of MPTP-lesioned rhesus monkeys, which demonstrated that GDNF did not diffuse effectively into the NHP caudate nucleus or putamen. This finding indicated that the success of intraventricular infusions in rodents might be a consequence of the much smaller diffusion distances within the rat brain. Furthermore, weight loss and dyskinesias remained recurrent complications in NHP studies.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here