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Neurotrophic Factors in Parkinson's Disease: Clinical Trials, Open Challenges and Nanoparticle-Mediated Delivery to the Brain.

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.

SUBMITTER: Bondarenko O

PROVIDER: S-EPMC8206542 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Silymarin is a bioactive constituent isolated from milk thistle (Silybum marinum). Since its discovery, silymarin has been considered a gold standard drug in treating ailments related to the liver, resulting from alcohol consumption and viral hepatitis. This hepatoprotective nature of silymarin arises out of antioxidative and tissue-regenerating properties of silymarin. However, several recent studies have established the neuroprotective link of silymarin, too. Thus, the current investigation was aimed at exploring the neuroprotective effect of nanosilymarin (silymarin encapsulated inside collagen-based polymeric nanoparticulate drug delivery system). The study aimed at bringing out the role of nanoparticles in enhancing the therapeutic effect of silymarin against neuronal injury, originating out of oxidative-stress-related brain damages in focal cerebral ischemia. Collagen-based micellar nanoparticles were prepared and stabilized using 3-ethyl carbodiimide-hydrochloride (EDC-Hcl) and malondialdehyde (MDA) as crosslinkers. Nanoparticles were characterized using dynamic light scattering (DLS), transmission electron microscopy (TEM), and Fourier transform infrared (FT-IR) spectroscopy techniques, and the size of nanoparticles was found to be around 48 nm. Male albino Wistar rats were pretreated with three different doses of nanosilymarin of 10, 100, and 1,000 ?g/kg b.wt and a dose of free silymarin of 100 mg/kg b.wt intraperitoneally (i.p.) for 7 days. Focal cerebral ischemia was induced using the middle cerebral artery occlusion (MCAO) model on the eighth day for 1 h followed by 24 h reperfusion. The animals were then evaluated for neurobehavioral, infarct analysis, biochemical, histopathological, and immunohistochemical studies. All the above parameters showed remarkable improvement in nanosilymarin-treated groups in comparison to the silymarin-treated group. Nanoparticle encapsulation of drug enhanced neuroprotection by increasing drug bioavailability and targeting. Thus, the present study concluded with satisfactory results, showing the critical role played by nanoparticles in improving the neuroprotection at very low drug doses.

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Neurotrophic Factors in Parkinson's Disease: Clinical Trials, Open Challenges and Nanoparticle-Mediated Delivery to the Brain.

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