From regenerative strategies to pharmacological approaches: can we fine-tune treatment for Parkinson's disease? (Starting my NAC again!)2022

[Bolt_Upright]

This new article covers combining Stem Cells Secretome (SCS) and NAC to treat PD.

From regenerative strategies to pharmacological approaches: can we fine-tune treatment for Parkinson's disease? ncbi.nlm.nih.gov/labs/pmc/a...

"Abstract

Parkinson's disease is the second most prevalent neurodegenerative disorder worldwide. Clinically, it is characterized by severe motor complications caused by progressive degeneration of dopaminergic neurons. Current treatment is focused on mitigating the symptoms through the administration of levodopa, rather than on preventing dopaminergic neuronal damage. Therefore, the use and development of neuroprotective/disease-modifying strategies is an absolute need that can lead to promising gains on translational research of Parkinson's disease. For instance, N-acetylcysteine, a natural compound with strong antioxidant effects, has been shown to modulate oxidative stress, preventing dopamine-induced cell death. Despite the evidence of neuroprotective and modulatory effects of this drug, as far as we know, it does not induce per se any regenerative process. Therefore, it would be of interest to combine the latter with innovative therapies that induce dopaminergic neurons repair or even differentiation, as stem cell-based strategies. Stem cells secretome has been proposed as a promising therapeutic approach for Parkinson's disease, given its ability to modulate cell viability/preservation of dopaminergic neurons. Such approach represents a shift in the paradigm, showing that cell-transplantation free therapies based on the use of stem cells secretome may represent a potential alternative for regenerative medicine of Parkinson's disease. Thus, in this review, we address the current understanding of the potential combination of stem cell free-based strategies and neuroprotective/disease-modifying strategies as a new paradigm for the treatment of central nervous system neurodegenerative diseases, like Parkinson's disease."

[Bolt_Upright]

So this idea is Secretone plus NAC:

"Stem Cells Secretome

In recent years, the use of SCS is looking as a promising therapeutic tool for central nervous system neurodegenerative diseases, like PD. Within such concept, the secretome of mesenchymal stem cells (MSCs) has been the focus of intense research on potential therapeutic strategies for CNS repair and regeneration (Teixeira and Salgado, 2020). In the past years, we have shown that the therapeutic properties of MSCs are closely related to their secretome - a mixture of released soluble and vesicular fractions of proteins and nucleic acids – with proven encouraging data in pre-clinical models for PD (Mendes-Pinheiro et al., 2019). In vitro, we have demonstrated positive effects of MSCs secretome in neuronal and glial survival and differentiation and axonal growth (Martins et al., 2017; Teixeira et al., 2017). We also showed that the treatment with the secretome of MSCs from bone marrow have promising effects in a rat pre-clinical model of PD, where sole administration lead to significant motor improvements and rescue of dopaminergic neurons (Teixeira et al., 2017, 2020; Mendes-Pinheiro et al., 2019). Using unbiased proteomics analysis, we identified in MSCs secretome the presence of important protective molecules such as DJ-1, TRXR1, PRDX1, brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), PEDF, Gal-1 and Cystatin C, which may explain the multi-target beneficial effects observed (Teixeira and Salgado, 2020).

In addition to MSCs, encouraging evidence have also demonstrated that the use of SCS from other stem cells sources such as neural progenitor cells (NPCs), also confer beneficial properties to Parkinson's treatment (Willis et al., 2020b). Indeed, we have revealed for the first time that the sole injection of human NPCs secretome in a 6-OHDA rat model of PD, provided support to promote dopaminergic neuronal survival, which consequently lead to an improvement on animal motor deficits (Mendes-Pinheiro et al., 2018). Actually, NPCs are believed to be neurotrophic factors secreting cells, capable of releasing neurotrophic components such as GDNF and BDNF that can sustain the growth and differentiation of dopaminergic (im)mature neurons in PD models, and regulate many biological processes, comprising cell survival, proliferation and differentiation, as well as immunomodulation, and regulation of the apoptotic process (Mendes-Pinheiro et al., 2018; Willis et al., 2020a). Although promising, the studies involving the action of NPCs secretome in PD are still limited, being too early to take sustainable conclusions (Willis et al., 2020a).

Such findings have driven SCS to be considered a promising and valuable therapeutic purpose for PD. With it, we expect to overcome the disadvantages of cell transplantation itself (high numbers of cells for transplantation; low rates of cell survival and engraftment upon transplantation), as well as the preceding differentiation processes. By overcoming these disadvantages with SCS-based approaches, it should be possible to develop a faster and reliable therapy, using off-the-shelf ready to use products.

N-Acetylcysteine

Both at the cellular and physiological levels, oxidative stress is considered to be a potential driver of PD progression. NAC is an old antioxidant nutraceutical with an ample spectrum of use, but with potential new tricks in nervous system regeneration. In fact, recent controlled and randomized clinical trials have demonstrated that intravenous administration of NAC increased blood redox rations of glutathione (Holmay et al., 2013) and may positively affect the dopaminergic system in patients with PD (Monti et al., 2019, 2016). These findings were supported by previous in vitro and rodent pre-clinical in vivo models of PD where NAC supplementation decreased the levels of brain aggregated alpha-synuclein, modulated the localization of NFkappaB and protected dopaminergic cells (Bagh et al., 2008; Clark et al., 2010; Berman et al., 2011). Additionally, NAC administration substantially increased brain synaptic and non-synaptic connections, diminished oxidative damage, raised brain synaptic mitochondrial complex I activity and anti-inflammatory protection and prevented reactive oxygen species accumulation (Mart??nez Banaclocha, 2000; Chen et al., 2007). The recent observed similar protective effects of NAC on oligodendrocytes and astrocytes (Shieh et al., 2019; Zhou et al., 2020) make NAC a promising multi-target prodrug in PD treatment."

I think if I was rich I could find a way to try this.