Neurogenesis

Programmed cell death, better known as apoptosis, is crucial in eliminating abnormal or unwanted cells in the body.^[2] In recent years, the complex pathways regulating apoptosis have been well-studied as potential therapy targets.^[2,10] Parkinson’s disease (PD) is no exception since the leading cause of this disorder is the death of dopamine-producing neurons in the brain (see Fig.1).^[1-4] PD is a debilitating neurodegenerative disorder that steals a person’s ability to control movement.^[8] Currently, levodopa (L-Dopa) is the most effective treatment for PD, helping in the improvement of the symptoms but not in the progression of the disease.^[3] In addition, the use of L-Dopa led to adverse reactions after long-term administration.^[3,7] Several studies propose using microRNAs (miRNAs) to inhibit the apoptosis of the dopamine-producing neurons found in PD.^[6-9] miRNAs are tiny molecules capable of regulating gene expression (molecular switches) in the most critical processes for cell survival, like proliferation, cell differentiation, and apoptosis when required.^[5-8]

Figure 1. The comparison between the normal functioning of dopaminergic neurons in healthy individuals vs in PD patients. 

For this reason, understanding the role of miRNAs in PD could be vital to developing new treatments to decrease the progression of the disorder. The apoptosis process is significant for eliminating unwanted cells.^[2] Therefore, using miRNAs as a therapy has the potential to inhibit unwanted cell death and induce apoptosis in abnormal cells as well.^[3-6] Understanding this interplay between miRNAs and apoptosis could lead to new treatment strategies for PD.^[7] Several investigations found that miRNAs have neuroprotection abilities, safeguarding neurons from apoptotic cell death.^[5] Alternatively, miRNAs promote apoptosis, thus eliminating damaged or dysfunctional neurons, which is crucial to clear cellular debris from microenvironments.^[5]

Some benefits of using miRNAs as a therapy for PD are the following: (1) miRNAs can target specific genes involved directly in the apoptotic pathway (specificity). (2) miRNAs are molecular switches, activating or inhibiting the apoptosis pathway. This adaptive characteristic is very convenient for this type of therapy since PD requires, in some cases, the inhibition of neuronal death (dopamine-producing neurons) and the activation of apoptosis in unwanted cells in the brain. (3) miRNAs can cross the blood-brain barrier and enter into cells, which is a challenge in developing neurodegenerative diseases. The apoptosis pathway accelerates the progression of PD by the direct dopamine depletion caused by the death of dopamine-producing neurons.^[4-6] As the disease progresses, more and more neurons are lost, leading to worsening symptoms and disability.

Mesenchymal stem cell-derived exosomes as a promising therapy for Parkinson’s and Alzheimer’s Disease.

Recently, investigators suggested using Mesenchymal stem cells (MSCs)–derived exosomes as a therapy for different conditions, including Parkinson’s Disease (PD).^[1,2,5] MSCs can be found in various body parts and specialize in different cell types depending on the body’s needs.^[1] These cells produce extracellular vesicles called exosomes that have been studied as an alternative medicinal agent because of their stability and biological prospect in terms of the substances they carry, like signaling molecules, cytokines, enzymes, and micro-RNA (miRNA).^[1,2,4] All these components are essential in maintaining cellular homeostasis, while the miRNA is more involved in regulating gene expression. ^[1,2,4] Many studies with MSCs have demonstrated several benefits in other neuropathological conditions. ^[1] One of the insights is that the MSCs have been pointed to activate different neuro-regeneration processes, opening a door for many possible ways to serve as promising therapies for future clinical trials. ^[1,3] Two targets for developing new treatments using MSCs are PD and Alzheimer’s disease (AD). ^[2,3,4,7] PD is characterized by the deterioration of dopaminergic neurons and the insufficiency of dopamine production. ^[3,6,9] Generally, the decrease of dopaminergic neurons is related to the accumulation of Lewy bodies (protein aggregates of α-synuclein) inside the neurons, which affects the normal functioning of those cells.^[9] Interestingly, MSCs-derived exosome seems to be able to decrease one of the leading causes of PD, neuroinflammation.^[2,5,10] On the other hand, AD is described as a brain illness that presents as neurological hallmarks the formation of amyloid plaques (Aβ) and neurofibrillary tangles causing synaptic loss.^[4,7,12]

Semax Stimulates Neurogenesis. 

“Here, we found that a single application of Semax (50 μg/kg body weight) results in a maximal 1.4-fold increase of BDNF protein levels accompanying with 1.6-fold increase of trkB tyrosine phosporylation levels, and a 3-fold and a 2-fold increase of exon III BDNF and trkB mRNA levels, respectively, in the rat hippocampus. Semax-treated animals showed a distinct increase in the number of conditioned avoidance reactions. We suggest that Semax affects cognitive brain functions by modulating the expression and the activation of the hippocampal BDNF/trkB system.” (18)

Cognition is a complex system encompassing processes such as episodic memory, working memory, executive function/inhibition, spatial learning, language/vocabulary comprehension, processing speed, and language/reading decoding. Changes in synaptic plasticity, the ability of the brain to change and adapt to new information, can be short lived from milliseconds to years. Short lived forms include facilitation, augmentation, and potentiation which enhances neurotransmitter release.

These dynamic changes represent the molecular basis for learning and memory. This synaptic plasticity can be influenced by several factors e.g., aging, diseases (obesity, diabetes, hypertension, dyslipidemia), toxins (smoking and alcohol), and exercise. Aging has been estimated to trigger performance decline with an incidence of mild cognitive impairment of 21.5–71.3 per 1000 person-years). Cortical thickness and subcortical volume are shrinking 0.5–1% annually as a morphological sign of cognitive decline with plaques and axonal degeneration. Dementia is diagnosed when the acquired cognitive impairment has become severe enough to compromise social and/or occupational functioning with increasing prevalence.

Worldwide, around 50 million people have dementia and, with one new case every three seconds, the number of people with dementia is set to triple by 2050. Thus, there is a huge need for new research in order to combat the above-mentioned metrics. The peptides below have undergone extensive research to help aid in the improvement for our neurocognitive system.

Selank

Both Selank and Semax are melanocortin’s and have pleiotropic effects involved in brain health and function. Selank by itself has traditionally been prescribed for anxiety and depression. Selank has pronounced anxiolytic activity and acts as a stable neuropsychotropic, antidepressant, and anti-stress medication.

Semax

Semax is used as a therapeutic with pathologies related to brain circulation dysfunction. As a combination, Selank/Semax has applications in improving learning processes, exploratory behavior, regeneration and development, nociceptive and in amatory processes, accelerate nerve regeneration and improve neuromuscular performance and overall neural health.

NAD+ is the second most abundant cofactor in the human body. Anti-aging therapies are becoming more mainstream as aging is now more often being viewed as a disease. Now that this transition is happening, the ability for NAD+ to activate PARPS, Sirtuins, and help with immune dysregulation has been thoroughly investigated and NAD+ and its precursors have been highly popularized. The clinical importance of maintaining cellular NAD+ levels was established early in the last century with the finding that pellagra, a disease characterized by diarrhea, dermatitis, dementia and death, could be cured with foods containing the NAD+ precursor niacin.

Additionally, cellular concentrations of NAD+ have been shown to decrease under conditions of increased oxidative damage such as occur during aging Altered levels of NAD+ have been found to accompany several disorders associated with increased oxidative/free radical damage including diabetes, heart disease, age-related vascular dysfunction, ischemic brain injury, misfolded neuronal proteins, and Alzheimer’s dementia. Interventions targeted at restoring NAD+ has been shown in animal models to support healthy aging and improve metabolic function, and dementia.

A need for NAD+ in muscle development, homeostasis, and aging

In a review study, researchers discuss the recent data that document conserved roles for NAD+ in skeletal muscle development, regeneration, aging, and disease as well as interventions targeting skeletal muscle and affecting NAD+ that suggest promising therapeutic benefits. The researchers also highlight gaps in our knowledge and propose avenues of future investigation to better understand why and how NAD+ regulates skeletal muscle biology.