RSS Feed Print
Edaravone and Alzheimer's disease
Lane Simonian
Posted: Tuesday, April 7, 2015 10:46 AM
Joined: 12/12/2011
Posts: 4986


I hate to include this one because it is a mouse study and more importantly edaravone can have some nasty side effects such as liver damage. Nevertheless, it illuminates the mechanisms needed to effectively treat Alzheimer's disease.

Prof Zhou said lessons learned from failures of current clinical trials suggest that targeting multiple key pathways of the Alzheimer’s Disease pathogenesis is necessary to halt and delay the disease progression. “Edaravone can suppress the toxic functions of amyloid beta to nerve cells – it is a free radical scavenger which suppresses oxidative stress that is a main cause of brain degeneration,” he said.

“The drug can suppress the production of amyloid beta by inhibiting the amyloid beta production enzyme. It also inhibits the Tau hyperphosphorylation which can generate tangles accumulated in the brain cells and disrupt brain functions.” Prof Zhou said that although he didn’t believe Alzheimer’s Disease could ever be cured, the drug was the best hope of attacking the debilitating disease through multiple signal pathways.

http://www.lifesciencesindex.com/5084/drug-discovery-gives-hope-to-halting-progression-of-alzheimers-disease

Half of this is true and half of it is not. The following statement is mostly true: "the drug can suppress the production of amyloid beta by inhibiting amyloid beta production enzyme. It also inhibits tau hyperphosphorylation which can generate tangles accumulated in the brain cells and disrupt brain functions." Edaravone does inhibit beta amyloid production by inhibiting the BACE enzyme and it also inhibits the hyperphosphorylation and nitration of tau proteins. The latter alone is sufficient to disrupt neurotransmissions and the transport of neurons in the brain--tangles are not required. Inhibiting beta amyloid production, on the other hand, is largely incidental to slowing the progression of Alzheimer's disease.

Here is the most accurate statement by the researchers: "Edaravone...is a free radical scavenger which suppresses oxidative stress that is the main cause of brain degeneration."

2005 Feb;48(2):283-90. Epub 2004 Dec 24.

The radical scavenger edaravone prevents oxidative neurotoxicity induced by peroxynitrite and activated microglia.


http://www.ncbi.nlm.nih.gov/pubmed/15695167

But edaravone is not the only compound that "suppresses oxidative stress that is the main cause of brain degeneration" and certainly not the safest. The researchers might be right: Alzheimer's disease may never be cured but its progression can be halted and partially reversed. And if close attention is paid to studies like this, the path to doing so suddenly becomes wide open.

Lane Simonian
Posted: Tuesday, April 7, 2015 11:37 PM
Joined: 12/12/2011
Posts: 4986


Here is Alzheimer's disease in a nutshell: p38 MAPK activation, peroxynitrite formation, caspase-3 activation, death of neurons. Peroxynitrite scavengers such as edaravone break this chain and partially reverse the damage that peroxynitrites do to the brain.

Caspase-3 is a key protease during apoptosis. The activated caspase-3 can enzymolyse specific substrates such as DNA-dependent protein kinase and sterol regulatory element binding protein, and induce apoptosis by changing its structure or affect specific signaling molecules. Caspase-3 expression and apoptosis of neural cells can be detected in the early period of traumatic brain injury, and the expression level of caspase-3 is related to the extent of brain injury.[] p38MAPK downstream signal transduction includes the activation of caspase-3 in the process of cerebral ischemia[] and the inhibition of P38MAPK phosphorylation can block the expression of caspase-3 and reduce neuronal apoptosis in model of neurodegenerative diseases.[] Our study found that the distribution of P38MAPK was almost the same as that of caspase-3. After treatment with edaravone, the expression of phosphorylated P38MAPK and caspase-3 declined dose-dependently. This indicates that the protective effect of edaravone on the brain is associated with the inhibition of the neuronal apoptosis pathway of P38MAPK and caspase-3.

In conclusion, edaravone can alleviate brain damage after DBI, inhibit p38MAP signal activation after early injury, reduce the expression of caspase-3, and promote the recovery of neurological function in the late period.


And from the titled article in the previous post:


The free radical scavenger edaravone has been used as an anti-oxidative agent in acute ischemic brain disorders. We examined the effect of edaravone on the production of nitric oxide (NO), reactive oxygen species (ROS) and proinflammatory cytokines by activated microglia, and we also examined its neuroprotective role in cortical neuronal cultures oxidatively stressed by the peroxynitrite donor N-morpholinosydnonimine (SIN-1) or activated microglia. Edaravone significantly suppressed the production of NO and ROS by activated microglia, though it did not suppress production of inflammatory cytokines. In addition, edaravone significantly suppressed neuronal cell death and dendrotoxicity induced by either SIN-1 or activated microglia in a dose-dependent manner. These results suggest that edaravone may function as a neuroprotective agent counteracting oxidative neurotoxicity arising from activated microglia, as occurs in either inflammatory or neurodegenerative disorders of the central nervous system.


It is just a matter of finding the most effective and safest peroxynitrite scavengers.