Dopaminergic neuroprotection and regeneration by neurturin assessed by using behavioral, biochemical and histochemical measurements in a model of progressive Parkinson’s disease

Oiwa, Yoshitsugu; Yoshimura, Ryo; Nakai, Kenta; Itakura, Toru

doi:10.1016/s0006-8993(02)02934-7

Cited by 97 publications

(60 citation statements)

References 49 publications

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“…It was shown that the NTN was efficiently delivered through the safely and reversibly FUS-opened BBB in the caudoputamen and substantia nigra after intravenous systemic administration, while bioeffects via downstream signaling to neuronal nuclei were also detected within 1 hour. Intrastriatal injections of NTN in rodent models of PD have demonstrated neuroprotective and neuroregenerative effects on dopaminergic nigrostiatal function, 28,29 and most recently, intraputamenal infusion in the globus pallidus of MPTP-lesioned rhesus monkeys showed behavioral improvement and elevated locomotor activity levels. 30 Nevertheless, in this study, it was shown that FUS in conjunction with microbubbles can induce high levels of NTN bioavailability through the safely opened BBB volume, and increased bioactivity, indicating the strong therapeutic potential for Parkinson's and other neurodegenerative diseases of this noninvasive drug delivery methodology.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Delivery and Bioactivity of the Neurturin Neurotrophic Factor through Focused Ultrasound—Mediated Blood—Brain Barrier Opening in vivo

Samiotaki

Acosta

Wang

et al. 2015

J Cereb Blood Flow Metab

102

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The blood-brain barrier (BBB) constitutes a major obstacle in brain drug delivery. Focused ultrasound (FUS) in conjunction with microbubbles has been shown to open the BBB noninvasively, locally, and transiently to allow large molecules diffusion. Neurturin (NTN), a member of the glial-derived neurotrophic factor (GDNF) family, has been demonstrated to have neuroprotective and regenerative effects on dopaminergic neurons in vivo using invasive drug delivery methods. The brain's ascending nigrostriatal pathway is severely damaged in Parkinson's disease (PD), and therefore the substantia nigra (SN) and striatal caudoputamen (CP) were selected as the target areas. The objective of the study was to investigate whether safe and efficient NTN delivery can be achieved through FUS-induced BBB opening via intravenous administration, and thus trigger the neuroregeneration cascade in the nigrostriatal pathway. After the optimization of FUS parameters and target locations in the murine brain, NTN bioavailability and downstream signaling were detected and characterized through immunostaining. FUS significantly enhanced the delivery of NTN compared with the direct injection technique, whereas triggering of the signaling cascade was detected downstream to the neuronal nuclei. These findings thus indicate the potential of the FUS method to mediate transport of proteins through the blood-brain barrier in a PD animal model.

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Section: Discussionmentioning

confidence: 99%

Enhanced Delivery and Bioactivity of the Neurturin Neurotrophic Factor through Focused Ultrasound—Mediated Blood—Brain Barrier Opening in vivo

Samiotaki

Acosta

Wang

et al. 2015

J Cereb Blood Flow Metab

102

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“…46 Neurturin has been shown to enhance survival of dopaminergic neurons both in vitro, and in rodent and monkey models of PD. [47][48][49][50][51][52][53] Evidence for restoration has also been found in rodents treated with 6-OHDA 52 and in aged monkeys, in which there is an age-related loss of dopaminergic phenotype. 54 In the later studies, an adenoassociated type 2 viral vector that encoded for human NRTN was injected unilaterally into the striatum of the aged rhesus monkeys.…”

Section: Neurturinmentioning

confidence: 90%

“…The evidence that it is neurorestorative is more limited. 52,54 The NRTN gene (alias NTN) is delivered in serotype 2 adeno-associated virus that specifically targets neurons. The vector is delivered by four stereotaxic injections into each putamen, with two infusions of vector at the inferior and superior part of the putamen.…”

Section: Gene Therapy With Neurturinmentioning

confidence: 99%

Treatment of Parkinson’s Disease with Trophic Factors

2008

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Summary: Trophic factors are proteins that support and protect subpopulations of cells. A number have been reported to act on dopaminergic neurons in vitro and in vivo, making them potential therapeutic candidates for Parkinson's disease. All of these candidate factors protect dopaminergic neurons if given prior to, or with, selective neurotoxins. Fewer trophic factors, primarily glial-derived neurotrophic factor (GDNF) and its relative, neurturin (NRTN; also known as NTN), have been shown to restore function in damaged dopamine neurons after the acute effects of neurotoxins have subsided. A major barrier to clinical translation has been delivery. GDNF delivered by intracerebroventricular injection in patients was ineffective, probably because GDNF did not reach the target, the putamen, and intraputaminal infusion was ineffective, probably because of limited distribution within the putamen. A randomized clinical trial with gene therapy for NRTN is underway, in an attempt to overcome these problems with targeting and distribution. Other strategies are available to induce trophic effects in the CNS, but have not yet been the focus of human research. To date, clinical trials have focused on restoration of function (i.e., improvement of parkinsonism). Protection (i.e., slowing or halting disease progression and functional decline) might be a more robust effect of trophic agents. Laboratory research points to their effectiveness in protecting neurons and even restoring dopaminergic function after a monophasic neurotoxic insult. Utility for such compounds in patients with Parkinson's disease and ongoing loss of dopaminergic neurons remains to be proven.

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“…Neurturin has been found to exert protective and functional effects on dopaminergic nigrostriatal neurones after 6-OHDA lesions of the adult rat MFB [79,80] or striatum [81,82] and after axotomy of the adult rat MFB [83]. The study by Rosenblad and colleagues directly compared the effects of neurturin with those of GDNF in the striatal 6-OHDA lesion model.…”

Section: Effects Of Neurturin In Vivomentioning

confidence: 99%