Our article this week talks about how the MAPK pathway is highly linked with several neurological diseases including Alzheimer’s Disease, Parkinson’s Disease, ALS – Almytotropic lateral sclerosis (or Lou Gehrig’s Disease), and cancer. A single pathway that is connected with so many influential diseases is exciting in that it offers a great deal of potential and a great challenge.
The MAPK Pathway
At the most basic level, the MAPK (Mitogen-Activated Protein Kinase) pathway is a set of proteins that activate one another by setting off and activating a kinase chain eventually leading to transcription factors in the nucleus being activated and the expression and coding of genes. More specifically, while not the only factor, it controls cell life and death.
This flow chart from this weeks article shows the three different MAPK protein pathways: ERK, p38, and JNK. In general, ERK can be associated with cell life or proliferation, while p38 and JNK can be associated with cell death or apoptosis. In Alzheimer’s Disease the ERK transcription is blocked and the p38/JNK pathway activated, which leads to cell degradation and apoptosis. In Parkinson’s Disease the activation of the p38/JNK pathway leads to the death of dopaminergic cells which lead to the symptoms associated with the disease. In ALS activation of the p38/JNK pathway leads to death of motor neurons. In Cancer, patients experience the over proliferation of cancer cells. In all of these cases there is malfunction of the MAPK pathway.
Research Possibilities
The link between all of these diseases and the MAPK pathway could be a great research opportunity because any new information that is acquired on the subject has the possibility of being applied to one or more of these diseases. This gives the prospect of moving forward in understanding of several diseases at the same time.
Using treatments of the MAPK pathway to find and treat the cause of the disease instead of treating symptoms . Since the MAPK pathway is highly linked to so many different diseases as well as cell life and death within the brain, selectivity of treatment would pose a dilemma. It would be unfortunate to find a way to treat one disease only to find that the treatment is leading to the cause of another disease or malfunction of the MAPK pathway in other parts of the brain.
The link between Alzheimer’s Disease, Parkinson’s Disease, ALS – Almytotropic lateral sclerosis (or Lou Gehrig’s Disease), and cancer through the MAPK pathway gives insight into how the brain works, and how these diseases effect the brain. It could in the future offers opportunities to find ways to treat the cause of the diseases, not only the symptoms. Other options such as gene therapy pose similar problems in that changing certain genes associated with the disease may help with the disease but cause unknown other problems in the future. There are still so many things we do now know or understand about how the brain works.
The Complexity of the MAPK Pathway
The key oxidant in many diseases is called peroxynitrite.
Pacher, et al. Nitric oxide and peroxynitrite in health and disease.
In Alzheimer’s disease, peroxynitrites oxidate (damage) receptors involved in short-term memory (muscarinic acetylcholine), alertness (dopamine), sleep (melatonin), smell (olfactory), social recognition (oxytocin), mood (opioid and serotonin), and brain growth (adrenergic). Peroxynitrites contribute to the hyperphosphorylation and nitration of tau proteins interferring with neurotransmissions. This toxin nitrates NMDA receptors allowing for the influx of calcium and the efflux of glutatmate both of which kill brain cells. Peroxynitrites oxidate choline transport systems and the enzyme choline acetyltransferase leading to a further shortage of acetylcholine which is a critical compound for short-term memory. Peroxynitrites also oxidate glucose transport systems leading to a lack of energy and focus and perhaps contributing to delusions.
Every peroxynitrite scavenger studied has reversed Alzheimer’s disease either in vitro, in animals, or in human beings. Methoxyphenols such as eugenol in rosemary essential oil and ferulic acid, coumaric acid, syringic acid, and vanillic acid in heat-processed ginseng are the best peroxynitrite scavengers and have led to significant improvements in cognitive function in Alzheimer’s patients in small-scale clinical trials (see Jimbo, et al. Effect of aromatherapy on patients with Alzheimer’s disease and Heo, et al. Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer’s disease).
In the case of Alzheimer’s disease you have to work upstream from MAPK. Inhibit phospholipase C gamma and/or beta and you inhibit the Protein kinase C mediated production of superoxide anions and inducible nitric oxide which combine to form peorxynitrites. Phospholipase C gamma can be inhibited by various fruits, vegetables, herbal teas, herbs, spices, and essential oils and phospholipase C gamma and beta activity can be inhibited by polyunsaturated fats such as fish oil.
Cole, Prevention of Alzheimer’s disease: Omega 3-fatty acid and phenolic anti-oxidant interventions.
And an excellent diagram showing the pathway that leads to Alzheimer’s disease (via protein kinase C) and the pathway that largely protects against Alzheimer’s disease (phosphatidylinositol3 kinase/Akt) see:
Phospholipase C signaling pathway–BioCarta.
The key to preventing or delaying the onset of Alzheimer’s disease is to inhibit the formation of peroxynitrites. The key to treating it is to scavenge and repair part of the damage caused by peroxynitrites.
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