Maybe I have finally figured this disease out

Lane Simonian

I have been trying to figure out Alzheimer's disease for nearly twenty years.  It comes down to this very simple observation:

"The inflammatory mediator peroxynitrite, when generated in excess, may damage cells by oxidizing and nitrating cellular components. Defense against this reactive species may be at the level of prevention of the formation of peroxynitrite, at the level of interception, or at the level of repair of damage caused by peroxynitrite."

Every treatment that slows down the production of peroxynitrite slows down the progression of Alzheimer's disease, but only those treatments which scavenge peroxynitrite and reverse part of the damage it does to the brain largely stabilizes Alzheimer's disease over long periods of time.

Here is a good example, Aricept/donepezil slows down oxidative stress by inhibiting the release of intracellular calcium and Namenda reduces oxidative stress by inhibiting NMDA receptors but both work much better with compounds that also scavenge peroxynitrite and repair part of the damage that it does to the brain:

Adding Chinese herbal medicine to conventional therapy brings cognitive benefits to patients with Alzheimer’s disease: a retrospective analysis

"MMSE change in groups with or without herbal medicine. a Patients with Alzheimer’s disease had a transient improvement in cognitive function with conventional therapy (CT), but declined to a level similar to no treatment after 18 months. CT supplemented with herbal medicine (CT + H) provided additional benefit. The effect from herbal medicines became more pronounced over time. Expected decline of MMSE were calculated by formula produced from previous data. b In subgroup analysis, patients with moderate AD (red lines) were initially more responsive to both CT + H and CT therapies than mild AD (blue lines) patients. Over the course of treatment, CT + H outperformed CT therapy, a substantial deceleration in cognitive decline being observed in patients with moderate AD, while a long-term stabilization effect being observed in the patients with mild AD. MMSE denotes mini-mental state examination."

A number of other examples of this exist.  For instance, compounds in panax ginseng that not only slow down the production of peroxynitrite but also scavenge it and reverse part of its damage led to improvements in cognitive function at 24 weeks that were sustained for two years.  Anavex 2-73 which like Aricept inhibits peroxynitrite formation by reducing the release of intracellular calcium, but unlike Aricept acts as a direct antioxidant largely stabilized cognitive function for three years.  The evidence for other treatments that do the same thing is more short-term but includes aromatherapy and GV-971 (a drug derived from brown algae).

The multiple failures in Alzheimer's drug development was not due to the intractable nature of the disease, it was due to efforts that nibbled around the edges of the disease rather than attacking its core.

Donr

Interesting to read Lane.

Lane Simonian

Thank you, Don.  Best wishes to you and your family.

BethL

Lane, my brain is healthy and I want to keep it that way. I know to exercise, eat healthy etc....are there supplements/specific foods/herbs that you, yourself would consider taking for the scavenging of peroxynitrite? You have a lot of knowledge; what do you do?

Crushed

The quote is from a piece  published almost twenty years ago 2003 Apr 11

Toxicol Lett

 Defenses against peroxynitrite: selenocompounds and flavonoids

Lars-Oliver Klotz  1 , Helmut Sies  

 

Abstract

The inflammatory mediator peroxynitrite, when generated in excess, may damage cells by oxidizing and nitrating cellular components. Defense against this reactive species may be at the level of prevention of the formation of peroxynitrite, at the level of interception, or at the level of repair of damage caused by peroxynitrite.

Dr Sies Coined the term Oxidative stress  However in the almost 20 years since there has been virtually no progress in finding  mechanisms to deal with it
 
An excellent review article describes the problems  

nature   nature reviews drug discovery

 Forman, H.J., Zhang, H. Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nat Rev Drug Discov 20, 689–709 (2021).

• Review Article
• Published: 30 June 2021

Targeting oxidative stress in disease: promise and limitations of antioxidant therapy
 

Oxidative stress is a component of many diseases, including atherosclerosis, chronic obstructive pulmonary disease, Alzheimer disease and cancer. Although numerous small molecules evaluated as antioxidants have exhibited therapeutic potential in preclinical studies, clinical trial results have been disappointing. A greater understanding of the mechanisms through which antioxidants act and where and when they are effective may provide a rational approach that leads to greater pharmacological success.

However, so far, the use of small molecules therapeutically has been disappointing, largely owing to overly optimistic and incorrect assumptions about how antioxidants work
  

 

It is essential to recognize the limitations that have led to failures in clinical trials and how antioxidant defences can be effective if one is realistic about where, when and to what extent oxidative stress is part of a disease  END OF QUOTE

  


  

Lane Simonian

I take panax ginseng each day (550 mg).  I sometimes take curcumin and Coenzyme Q10.  I occasionally do aromatherapy, which may or may not work as well at prevention.  There are absorption issues with curcumin which may be improved by using pepper.  

I have long transposed letters and numbers, but these days I am often making the wrong word choices.  That seems to have lessened somewhat since I started taking the panax ginseng about a year ago.

Lane Simonian

I like the quote, Crushed.  A few years back someone asked me if Alzheimer's disease is primarily a disease of oxidative stress would not any antioxidant work.  But there are all sorts of reasons why most antioxidants don't work in the treatment of Alzheimer's disease: problems in absorption, impaired transportation systems within the body, metabolism issues (sometimes the antioxidant is metabolized into an oxidant) to name a few.

You are my favorite critic, Crushed.  You always attack the science and not me as a person.