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Parkinson‘s disease (PD) is the second-most common neurodegenerative disorder that affects 2–3% of the population ≥65 years of age (Poewe, Seppi, Tanner et al., 2017). At the same time, 3 out of 1000 individuals worldwide are suffering from Alzheimer’s Disease (AD), this is expected to increase to 12 per 1000 by the year 2050 (Brookmeyer et al., 2007).
Both diseases are characterized clinically by a progressive decline in mental and cognitive ability. AD begins with impairment in the part of the brain responsible for learning, memorizing, thinking, and planning (Hadavi, & Poot, 2016), while PD is given by a Neuronal loss in the substantia nigra – part of the brain where dopamine neurons are found – causing striatal dopamine deficiency, and intracellular inclusions, this leads to shaking, stiffness, and difficulty with walking, balance, and coordination (Poewe, Seppi, Tanner, et al., 2017). In recent years, the area of biomedicine known as Tissue Engineering and Biomaterials has investigated various methods to repair brain damage and drug delivery for the treatment of neurodegenerative diseases, but there are still many problems to solve.
Figure 1. Blood brain barrier. Section of a blood vessel in the brain of a mouse (black), lined with endothelial cells surrounded by glial cells (green) forming an impermeable layer between the brain and bloodstream.
One of the main obstacles in the treatment of Central Nervous System (CNS) diseases is the low permeability of the blood-brain barrier (BBB) – a set of tissues that separate the bloodstream from the brain and functions as an immunological and metabolic barrier. Its purpose is to protect the brain from toxic substances preventing the release of drugs applied intravenously for the treatment of CNS diseases such as Alzheimer‘s and Parkinson‘s. One of the main objectives in neurology is to deliver drugs to the brain while crossing this barrier effectively, which is why there have been multiple investigations on this subject (Loch, & Koepp, 2010).
For the treatments to successfully pass the BBB and also to represent an effective long-term application, different materials have been tested such as a self-assembling peptide hydrogel system combined with curcumin – polyphenol received from dried rhizozomes of the herb Curcuma longa Linn, a member of the ginger family. The system has a minimally invasive delivery with the advantages of having curcumin as a stabilizer with an adequate controlled release.
Curcumin has proven to stop the cognitive decline and can even reverse the damage of AD and PD for its neuroprotective (Bordoni et al, 2020) and anti-inflammatory properties. Unfortunately, it lacks water solubility and has a relatively low bioavailability, affecting its therapeutic use. Therefore, a vehicle that delivers it to the desired point is needed, increasing its permeability. Peptide hydrogels have been selected for this task because they display shear-thinning and immediate recovery properties that make them excellent candidates for injectable therapies (Altunbas, Lee, Rajasekaran, Schneider & Pochan, 2011). But it is still necessary to carry out more research on this self-assembling peptide hydrogel system and the immune response it triggers in the BBB.
Neurodegenerative diseases and their progression are also related to changes in nerve growth factor (NGF) levels. Parkinson’s disease presents a deficiency of NGF, and Alzheimer’s disease is characterized by the loss of cholinergic cells – cells that release acetylcholine, a neurotransmitter that assists in the transmission of neuronal impulses. Therefore, the most promising treatment so far is the use of NGF, because it is essential for the survival of cholinergic neurons (Kurakhmaeva et al, 2009), and its administration prevents the degeneration of dopaminergic neurons. However, NGF lacks the ability to cross the BBB.
Research from different authors (Kurakhmaeva et al, 2009) show that poly (butyl cyanoacrylate) nanoparticles (PBCA NPs) are the best transport method to carry out the NGF release in the brain. Kurakhmaeva et al induced AD and PD in mice to prove different formulations of NGF using PBCA NP as carriers. Some of the PBCA NP were coated with polysorbate 80. The use of polysorbate 80 was proposed to enhance the uptake of PBCA NPs by the endothelial cells of the brain.
Figure 2. Administering Texas red dextran alone remains in the blood vessel (A). PBCA NPs coated with polysorbate 80 transporting Texas red dextran through the BBB (B).
The results obtained by Kurakhmaeva et al. (2009) demonstrated that after the intravenous injection of NGF with coated PBCA NP, higher concentrations of NGF were found in the brain of the animals and the tremors decreased, making it a potential candidate and a possible treatment for neurodegenerative diseases such as PD and AD. One of the points in favor of PBCA NP is that, in addition to being able to transport NGF to the central nervous system through the BBB, they are also capable of transporting larger molecules, such as neurotrophic peptides, which are the proteins that help to the survival and differentiation of existing neurons, enhancing the growth of new neurons and synapses – connection between neurons.
Although there are many advancements in the treatment of AD and PD, there are still many opportunities to increase the effectiveness of treatments to even cure them, and allow them to work in the long run. There is also still a lot of research field in the ways of administration of these treatments, since they tend to be highly invasive due to the nature of the diseases.
Until now, PBCA Nanoparticles as drug carriers may represent a light of hope in the treatment of neurodegenerative diseases, transporting NGF through the BBB into the brain. This may slow down the progression of AD and PD, improving skills of recognition and memory in the case of AD, and reducing symptoms of PD, such as oligokinesia – rapid decreased amplitude and velocity of the repeated movements –, rigidity and tremor. A cure for these diseases may not yet be found, but the reduction of these symptoms makes it possible to improve the quality of life of people who suffer from these diseases and their families.
References
Altunbas, A., Lee, S.J., Rajasekaran, S.A., Schneider, J.P., Pochan, D.J. (2011) Encapsulation of curcumin in self-assembling peptide hydrogels as injectable drug delivery vehicles. Biomaterials 2011, 32, 5906–5914.
Bordoni, M., Scarian, E., Rey, F., Gagliardi, S., Carelli, S., Pansarasa, O., & Cereda, C. (2020). Biomaterials in neurodegenerative disorders: A promising therapeutic approach. International journal of molecular sciences, 21(9), 3243.
Brookmeyer, R., Johnson, E., Ziegler‐Graham, K.,& Arrighi, H. M. (2007). Forecasting the global burden of Alzheimer’s disease. Alzheimer’s & Dementia, 3(3), 186-191.
Hadavi, D., & Poot, A. A. (2016). Biomaterials for the Treatment of Alzheimer’s Disease. Frontiers in bioengineering and biotechnology, 4, 49.
Kurakhmaeva, K. B., Djindjikhashvili, I. A., Petrov, V. E., Balabanyan, V. U., Voronina, T. A., Trofimov, S. S., Kreuter, J., Gelperina, S., Begley, D., & Alyautdin, R. N. (2009). Brain targeting of nerve growth factor using poly(butyl cyanoacrylate) nanoparticles. Journal of Drug Targeting, 17(8), 564–574.
Loch, G., & Koepp, J. (2010). The blood-brain barrier and drug delivery in the central nervous system. Escuela Nacional Superior de Minas. ID: ibc-86707
Poewe, W., Seppi, K., Tanner, C., et al. (2017). Parkinson disease. Nat Rev Dis Primers 3, 17013. DOI: https://doi.org/10.1038/nrdp.2017.13
About the authors
Ana María González Cajica
8th semester student in Biomedical Engineering, member of the SOMIB-UDLAP Student Chapter.
ana.gonzalezca@udlap.mx
Karla Isela Méndez Elías
8th semester student in Biomedical Engineering.
karla.mendezes@udlap.mx
Ana Paola Romero Carmona
8th semester student in Biomedical Engineering.
ana.romeroca@udlap.mx
Last modified: 13 mayo, 2021