Scientists Produce First Known Neuroprotective Compound for Parkinson's
 

CAN WE GET MJFF TO SPEED THIS UP?

http://www.eurekalert.org/pub_releas...-src021111.php

"Scientists from the Florida campus of The Scripps Research Institute have produced the first known compound to show significant effectiveness in protecting brain cells directly affected by Parkinson's disease, a progressive and fatal neurodegenerative disorder.

Although the findings were in animal models of the disease, the effectiveness of the compound, combined with its potential to be taken orally, offers the tantalizing possibility of a potentially useful future therapy for Parkinson's disease patients. The results were published in two separate studies in the journal ACS Chemical Neuroscience.

"These studies present compelling data on the first oral, brain-penetrating inhibitor to show significant efficacy in preventing neurodegeneration in both mouse and rat models of Parkinson's disease," said team leader Philip LoGrasso, a professor in the Department of Molecular Therapeutics and senior director for drug discovery at Scripps Florida. "The compound offers one of the best opportunities we have for the development of an effective neuroprotective treatment."

The new small molecule—labeled SR-3306—is aimed at inhibiting a class of enzymes called c-jun-N-terminal kinases (JNK). Pronounced "junk," these enzymes have been shown to play an important role in neuron (nerve cell) survival. As such, they have become a highly viable target for drugs to treat neurodegenerative disorders such as Parkinson's disease.

"A drug like SR-3306 that prevents neurodegeneration would be a quantum leap in the clinical treatment of Parkinson's because all current therapies treat only the symptoms of the disease, not the underlying pathologies," LoGrasso said.

(snip)

The SR-3306 compound, which has been in development at Scripps Florida for several years, performed well in both cell culture and animal models. In cell culture, the compound showed greater than 90 percent protection against induced cell death of primary dopaminergic neurons, while in mouse models of induced neuron death, the compound showed protective levels of approximately 72 percent.

The scientists went one step further, testing the new compound in a rat model, which duplicates the physical symptoms often seen with the human disease—a pronounced and progressive loss of motor skills. The results showed SR-3306 provided a protection level of approximately 30 percent in the brain, a level that reduced the dysfunctional motor responses by nearly 90 percent.

"It was a surprise that level of neuroprotection reduced the behavioral impact so strongly," LoGrasso said, "but it's indicative of how it might perform in human patients. While SR-3306 doesn't represent a cure, it does appear to have the potential of stopping the progression of the disease."

Great news!
 

This is so promising because it's a small molecule, and we've been trying for years to find a molecule small enough to get past the blood brain barrier (BBB).

Ron - Rick - olsen - other watchdogs - what do you know about this?

Peggy

Curcumin prevents dopaminergic neuronal death through inhibition of the JNK
 

Thank you Caldeerstar.
While waiting for this promising drug (I expect 5+ years waiting time), I am taking curcumine which the following research claims to do the same job of inhibiting JNK enzemes implicited in cell death !

Curcumin prevents dopaminergic neuronal death through inhibition of the c-Jun N-terminal kinase pathway.Yu S, Zheng W, Xin N, Chi ZH, Wang NQ, Nie YX, Feng WY, Wang ZY.

Key Laboratory of Cell Biology of Ministry of Public Health of China, Laboratory of Cell Engineering and Therapy of Institute of Tissue Engineering, China Medical University, Shenyang, PR China.

Abstract
Recent studies have shown that the c-Jun N-terminal kinase (JNK) signaling pathway is involved in dopaminergic neuronal degeneration, and direct blockade of JNK by specific inhibitors may prevent or effectively slow the progression of Parkinson disease (PD). Previous studies have revealed that the natural phenolic compound curcumin can reduce inflammation and oxidation, which makes it a potential therapeutic agent for neurodegenerative diseases. In this study, we investigated whether curcumin protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP) or 1-methyl-4-phenylpyridnium ion- (MPP(+)) induced dopaminergic neurotoxicity in C57BL/6N mice or SH-SY5Y cells by inhibiting JNK pathways both in vivo and in vitro. Curcumin treatment significantly improved behavioral deficits, and enhanced the survival of tyrosine hydroxylase-positive neurons in the substantia nigra (SN) in the MPTP-induced PD model mice. Most importantly, curcumin treatment significantly inhibited MPTP/MPP(+)-induced phosphorylation of JNK1/2 and c-Jun, and cleaved caspase-3. Our study suggests that the neuroprotective effect of curcumin is not related simply to its antiinflammatory and antioxidant properties, but involves other mechanisms, particularly by targeting the JNK pathways.

imark3000, could you share some specifics of your curcumin supplementation: What brand of curcumin do you take, how many mgs. and how often?
Thanks so much,
John

John:
 

I take 875 mg of curcumin daily ordered from Swanson Health website. I believe that few members of this forum do the same. It is recommended to take it with Bioperine for absorbtion enhancement which I also order from Swanson.
I must add that I take many supplements but I cannot testify objectively to their effect on my PD but I think they are at least not harmful as I maintain general excelent health.
Good luck.
Imad

biopene and MAO B inhibitors
 

If one takes an MAO B inhibitor such as Azilect or selegiline, biopene (pepper) is supposedly not a good idea. seems pepper is a natural MAO B inhibitor.
Is this just academic, MrsD or olcs?

Azilect and Bioperine
 

Imad and Olsen, thanks for the guidance. Since I do in fact take Azilect, I will err on the side of caution and take circumin without bioprene.

sr 3306 study references
 

hi peg, found the following with references to the 2 studies on SR 3306:

The new studies are part of a $7.6 million multiyear grant awarded to LoGrasso in 2008 by the National Institutes of Neurological Disorders and Stroke (NINDS). The grant will enable Scripps Research and potential partners to file an application for an investigational new drug (IND)—the first step in the lengthy clinical trials process required by the U.S. Food and Drug Administration before a new drug can be brought to market.

The first authors of the study, “Small Molecule c-jun-N-terminal Kinase (JNK) Inhibitors Protect Dopaminergic Neurons in a Model of Parkinson’s Disease,” are Jeremy W. Chambers and Alok Pachori of Scripps Research. Other authors include Shannon Howard, Michelle Ganno, Donald Hansen Jr., Ted Kamenecka, Xinyi Song, Derek Duckett, Weimin Chen, Yuan Yuan Ling, Lisa Cherry, Michael D. Cameron, Li Lin, and Claudia H. Ruiz, also of Scripps Research. See article
http://pubs.acs.org/doi/abs/10.1021/cn100109k

http://pubs.acs.org/doi/abs/10.1021/cn1001107
The first author of the study, “JNK Inhibition Protects Dopamine Neurons and Provides Behavioral Improvement in a Rat 6-hydroxydopamine Model of Parkinson’s Disease,” is Candice E. Crocker of Dalhousie University, Halifax, Nova Scotia, Canada. Other authors include Susan Khan and Michael D. Cameron of Scripps Research, and Harold A. Robertson and George S. Robertson of Dalhousie. See article
http://pubs.acs.org/doi/abs/10.1021/cn1001107


Both studies were supported by the National Institutes of Health. Harold A. Robertson and George S. Robertson were supported by funding from the Atlantic Innovation Fund.

Contact: Mika Ono – Scripps Research Institute
Source: Scripps Research Institute

CEP-1347 was kinases inhibitor
 

Quote about the CEP-1347 molecule before it went into human clinical trials (~2000):

"Neurons undergoing apoptosis can be rescued by trophic factors that simultaneously increase the activity of extracellular signal-regulated kinase (ERK) and decrease c-Jun N-terminal kinase (JNK) and p38. We identified a molecule, CEP-1347 (KT7515), that rescues motoneurons undergoing apoptosis and investigated its effect on ERK1 and JNK1 activity."

http://www.jneurosci.org/cgi/content/short/18/1/104

The CEP-1347 (PRECEPT) clinical trial 2002-2005 was a kinases inhibitor that showed great promise - in animal studies it protected and also rescued existing neurons. CEP-1347 - a small molecule - was taken orally (it DID pass the BBB). Unfortunately it failed in humans.

Here is wishing for success for this new molecule.

Jean

Fyi...
 

This is not MJFF-funded work although we are funding Scripps Florida/LoGrasso to work on a LRRK2-related target. We have been in touch with this team and their JNK efforts. Because their program is fully funded by NIH, they didn't need/seek MJFF funds for any of this work.

However, while this general pathway is interesting and may be worthwhile/relevant, I think the claim of "First Known Neuroprotective Compound for Parkinson's" based on rodent data is overstated.

Debi