Abstract
Neurotrophic factors (NTFs) are small secreted proteins that support the development, maturation and survival of neurons. NTFs injected into the brain rescue and regenerate certain neuronal populations lost in neurodegenerative diseases, demonstrating the potential of NTFs to cure the diseases rather than simply alleviating the symptoms. NTFs (as the vast majority of molecules) do not pass through the blood–brain barrier (BBB) and therefore, are delivered directly into the brain of patients using costly and risky intracranial surgery. The delivery efficacy and poor diffusion of some NTFs inside the brain are considered the major problems behind their modest effects in clinical trials. Thus, there is a great need for NTFs to be delivered systemically thereby avoiding intracranial surgery. Nanoparticles (NPs), particles with the size dimensions of 1-100 nm, can be used to stabilize NTFs and facilitate their transport through the BBB. Several studies have shown that NTFs can be loaded into or attached onto NPs, administered systemically and transported to the brain. To improve the NP-mediated NTF delivery through the BBB, the surface of NPs can be functionalized with specific ligands such as transferrin, insulin, lactoferrin, apolipoproteins, antibodies or short peptides that will be recognized and internalized by the respective receptors on brain endothelial cells. In this review, we elaborate on the most suitable NTF delivery methods and envision “ideal” NTF for Parkinson’s disease (PD) and clinical trial thereof. We shortly summarize clinical trials of four NTFs, glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), platelet-derived growth factor (PDGF-BB), and cerebral dopamine neurotrophic factor (CDNF), that were tested in PD patients, focusing mainly on GDNF and CDNF. We summarize current possibilities of NP-mediated delivery of NTFs to the brain and discuss whether NPs have impact in improving the properties of NTFs and delivery across the BBB. Emerging delivery approaches and future directions of NTF-based nanomedicine are also discussed.
Highlights
Potential of Neurotrophic Factors in Neurodegenerative Diseases and Open ChallengesNeurotrophic factors (NTFs) are typically proteins of 10 to 35 kDa in molecular weight that support the development, differentiation, survival and plasticity of neurons (Huttunen and Saarma, 2019)
its efficiency is a sum of several components
Very few studies have so far addressed all of these components
Summary
Potential of Neurotrophic Factors in Neurodegenerative Diseases and Open Challenges. All commercial and most of the emerging therapeutic approaches alleviate the symptoms of neurodegenerative diseases without curing them, while NTFs are able to slow down neurodegeneration and reverse the diseases at least in certain animal models and in some clinical trials (Lu et al, 2013; Chmielarz and Saarma, 2020). (b) Decrease of NTF levels or knockdown of their receptors results in neuronal loss and other disease-related outcomes. Decreased levels of NTFs have been found in the brains of AD, HD, and PD patients (Rinne et al, 1989; Lorigados Pedre et al, 2002), while supplementation of NTFs can protect affected neurons in the animal models of neurodegenerative diseases. In mice deficient in NTFs or their receptors disease-related neurons are often lost or affected (Kramer et al, 2007; Lindahl et al, 2020)
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