Chapter 9 - Neurotrophic Factors and Neurodegenerative Diseases: A Delivery Issue
Introduction
Due to their potential in providing symptomatic relief and in acting disease's modifying agents, neurotrophic factors (NTFs) are potentially major players in therapeutic interventions for neurodegenerative disorders like Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and many other neurodegenerative pathologies. Despite the incomplete understanding of the NTF role in neurological diseases, several neurotrophins (as nerve growth factor, NGF; brain-derived neurotrophic factor, BDNF; neurotrophin-3, NT-3; neurotrophin-4; NT-4), glial cell line-derived neurotrophic factor (GDNF), and neurokines (as ciliary neurotrophic factor, CNTF) belonging to the wide NTF family, were described in several in vitro and in vivo experiments of different pathologies aiming to obtain prevention and therapeutic efficacy on neuronal survival (Aron and Klein, 2011). These molecules, due to their distinct neuroprotective properties, demonstrated the cumulative effect of curbing the disease progression and allaying existing symptoms. An extensive literature is given regarding NTF application (as single molecule or in mixture, commercially named Cerebrolysin®) in spinal cord brain injury (Sharma, 2007, Sharma et al., 2010), showing high potential in neurorestoration.
Due to the NTF limits, such as their inability to cross the blood–brain barrier (BBB), their poor stability in fluid environment, the limited diffusion through the brain parenchyma, and the side effects associated with the binding with extra-target receptors, a numbers of papers and researches aimed to find a potentially efficacious strategy for NTF application in therapy.
This review will focalize the discussion on the evolution of the delivery strategies of NTFs on brain, underlining the merits and limits of technological–biotechnological–pharmaceutical research over the past 10–15 years.
Initially, we start discussing the first experiments by using direct free NTF intracerebroventricular (ICV) or intrastriatal administration in different neurodegenerative diseases. In the second section, we analyzed the literature data on the biotechnological “ex vivo” gene therapy approach and pharmaceutical technological approach by using nonviral exogenous transporters.
Section snippets
HD and NTFs
HD is an autosomal dominant hereditary neurodegenerative disorder characterized by chorea (excessive, spontaneous, irregularly timed abrupt movements), disturbed voluntary motor performance, cognitive impairment, and dementia. With an incidence of 4–10 per 100,000, Huntington afflicts approximately 50,000 patients both in Europe and in the United States and another 250,000 persons are genetically at risk. Although the average age of onset is approximately 40 years, the disease may begin at any
NTF Delivery Approaches: Evolution in Therapies
Whereas the attractiveness of NTFs as preventive and curative for a wide range of neurodegenerative diseases, researchers are proposing the application of new and more effective strategies to improve the release of these factors. Besides the application of viral vectors, which are deeply discussed in other chapters (Bjorklund and Kirik, 2009, Bjorklund and Kordower, 2010, Deierborg et al., 2008), naked and/or encapsulated cells secreting NTFs (ex vivo gene therapy/cell-based therapy) and
Conclusion
The extreme large number of experiments on AD, PD, HD, ALS, and other neurodegenerative diseases produced a plethora of data on the efficacy, the safety, and the potential applicability of NTF approach as therapeutic treatment. If it is clear that NTF strategies really represent a tremendous option for neuroregeneration at various levels of neuropathology, several drawbacks in their applicability will be demonstrated and recorded. These limitations, ranging from NTF side effects to their poor
References (215)
- et al.
Drug metabolism and pharmacokinetics, the blood–brain barrier, and central nervous system drug discovery
NeuroRx
(2005) - et al.
Neuroprotective strategies for basal ganglia degeneration: Parkinson's and Huntington's diseases
Prog. Neurobiol.
(2000) - et al.
Glial cell line-derived neurotrophic factor attenuates the excitotoxin-induced behavioural and neurochemical deficits in a rodent model of Huntington's disease
Neuroscience
(1997) - et al.
Repairing the parkinsonian brain with neurotrophic factors
Trends Neurosci.
(2011) - et al.
The blood–brain barrier: an overview, structure, regulation, and clinical implications
Neurobiol. Dis.
(2004) - et al.
Comparative study of GDNF delivery system for the CNS: polymer rods, encapsulated cell and lentiviral vectors
J. Control. Release
(2003) - et al.
Macrophage-mediated GDNF delivery protects against dopaminergic neurodegeneration: a therapeutic strategy for Parkinson's disease
Mol. Ther.
(2010) - et al.
Scientific rationale for the development of gene therapy strategies for Parkinson's disease
Biochim. Biophys. Acta
(2009) - et al.
Neural transplantation for the treatment of Parkinson's disease
Lancet Neurol.
(2003) - et al.
Staging of brain pathology related to sporadic Parkinson's disease
Neurobiol. Aging
(2003)
Delivering neuroactive molecules from biodegradable microspheres for application in central nervous system disorders
Biomaterials
Neurotrophic factors for the treatment of Parkinson's disease
Parkinsonism Relat. Disord.
Effect of GDNF-releasing biodegradable microsphere on the function and the survival of intrastriatal fetal ventral mesencephalic cell grafts
Eur. J. Pharm. Biopharm.
Effects of intrastriatal GDNF on the response of dopamine neurons to 6-hydroxydopamine: time course of protection and neurorestoration
Brain Res.
Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis
Exp. Neurol.
Astrocyte delivery of glial cell line-derived neurotrophic factor in a mouse model of Parkinson's disease
Exp. Neurol.
Hyperplastic changes within the leptomeninges of the rat and monkey in response to chronic intracerebroventricular infusion of nerve growth factor
Exp. Neurol.
Emerging restorative treatments for Parkinson's disease
Prog. Neurobiol.
Pharmacokinetics of intrathecally applied BDNF and effects on spinal motoneurons
Exp. Neurol.
Ex vivo delivery of GDNF maintains motor function and prevents neuronal loss in a transgenic mouse model of Huntington's disease
Exp. Neurol.
Implantation of polymer-encapsulated human nerve growth factor-secreting fibroblasts attenuates the behavioral and neuropathological consequences of quinolinic acid injections into rodent striatum
Exp. Neurol.
Cellular delivery of CNTF but not NT-4/5 prevents degeneration of striatal neurons in a rodent model of Huntington's disease
Cell Transplant.
Dose–response comparison of recombinant human nerve growth factor and recombinant human basic fibroblast growth factor in the fimbria fornix model of acute cholinergic degeneration
Brain Res.
Distribution of radioiodinated recombinant human nerve growth factor in primate brain following intracerebroventricular infusion
Exp. Neurol.
Ex vivo and in vitro studies of transgene expression in rat astrocytes transduced with lentiviral vectors
Exp. Neurol.
In vivo evaluation of poly-lactide-co-glycolide porous conduits for peripheral nerve regeneration
Biomaterials
Biocompatibility of implantable synthetic polymeric drug carriers: focus on brain biocompatibility
Biomaterials
Implanted BDNF-producing fibroblasts prevent neurotoxin-induced serotonergic denervation in the rat striatum
Mol. Brain Res.
Cell-mediated delivery of brain-derived neurotrophic factor enhances dopamine levels in an MPP+ rat model of substantia nigra degeneration
Cell Transplant.
Effective GDNF brain delivery using microspheres-A promising strategy for Parkinson's disease
J. Control. Release
GDNF improves dopamine function in the substantia nigra but not the putamen of unilateral MPTP-lesioned rhesus monkeys
Brain Res.
N-terminal tripeptide of IGF-1 (GPE) prevents the loss of TH positive neurons after 6-OHDA induced nigral lesion in rats
Brain Res.
Neurotrophins prevent death and differentially affect tyrosine hydroxylase of adult rat nigrostriatal neurons in vivo
Exp. Neurol.
Nerve growth factor effects on cholinergic neurons of neostriatum and nucleus accumbens in the adult rat
Neuroscience
Ciliary neurotrophic factor prevents neuronal degeneration and promotes low affinity NGF receptor expression in the adult rat CNS
Neuron
The neurotrophin NT4/5, but not NT3, enhances the efficacy of nigral grafts in a rat model of Parkinson's disease
Brain Res.
Nerve growth factor increases choline acetyltransferase but not survival or fiber outgrowth of cultured fetal septal cholinergic neurons
Neuroscience
Gene therapy using lactoferrin-modified nanoparticles in a rotenone-induce chronic Parkinson model
J. Neurol. Sci.
Intracerebral NGF infusion induces hyperinnervation of cerebral blood vessels
Neurobiol. Aging
Long term effect of intrastriatal glial cell-line derived neurotrophic factor releasing microspheres in a partial rat model of Parkinson's disease
Neurosci. Lett.
Huntington disease in Georgia: age at onset
Am. J. Hum. Genet.
Intrathecal delivery of CNTF using encapsulated genetically modified xenogenic cells in amyotrophic lateral sclerosis patients
Nat. Med.
Neuroprotection through delivery of glial cell line-derived neurotrophic factor by neural stem cells in a mouse model of Parkinson's disease
J. Neurosci.
A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis
Neurology
Ciliary neurotrophic factor protects striatal output neurons in an animal model of Huntington disease
Proc. Natl. Acad. Sci. USA
A unifying hypothesis for the cause of amyotrophic lateral sclerosis, parkinsonism, and Alzheimer's disease
Ann. Neurol.
Survival effect of ciliary neurotrophic factor (CNTF) on chick embryonic motoneurons in culture: comparison with other neurotrophic factors and cytokines
J. Neurosci.
Neuroprotective gene therapy for Huntington's disease using a polymer encapsulated BHK cell line engineered to secrete human CNTF
Hum. Gene Ther.
Neural progenitor cells engineered to secrete GDNF show enhanced survival, neuronal differentiation and improve cognitive function following traumatic brain injury
Eur. J. Neurosci.
Autonomic dysfunction in ALS: a preliminary study on the effects of intrathecal BDNF
Amyotroph. Lateral Scler. Other Motor Neuron Disord.
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