05 Oct 2012

An agent that keeps young neurons alive appears to do the same for aging neurons that are taking a beating in mouse models of both Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). Two companion studies report as much in the October 1 Proceedings of the National Academy of Sciences USA online. Researchers developing the compound are looking for collaborations to test it in mouse models of other neurodegenerative conditions, including Alzheimer’s disease and traumatic brain injury. Meanwhile, chemists are tweaking the molecule in the hopes of producing an ideal drug candidate for human trials.

“These two papers offer hope that we can develop a neuroprotective drug to treat human neurodegenerative disease,” said Andrew Pieper, senior author on both papers together with Steven McKnight and Joseph Ready at the University of Texas Southwestern Medical Center in Dallas. The drug they tested came out of a previous in-vivo screen. McKnight and Pieper, who recently moved to the University of Iowa Carver College of Medicine in Iowa City, tested 1,000 compounds as they searched for chemicals that would support survival of maturing hippocampal neurons in mice. Pieper named his top candidate P7C3 because it was the third compound in the seventh pool of 10 he analyzed (see ARF related news story on Pieper et al., 2010).

P7C3 is a carbazole, consisting of three carbon rings. Chemists in Ready’s lab have since swapped out molecular elements to create nearly 300 variants of P7C3 (MacMillan et al., 2011). A20, the twentieth such analogue, shows the most promise, rescuing more young hippocampal neurons than P7C3. In the current two studies, the researchers saw that A20 also saves struggling neurons in diseases of aging.

In the ALS study, first author Rachel Tesla gave A20 to mice expressing the mutant ALS gene superoxide dismutase 1 (SOD1). Staining spinal cord sections from treated and control mSOD1 mice, she found that the former possessed up to twice as many spinal motor neurons as the latter. She also found that when given A20, mice walked more normally and hung on to a rotating rod longer than did untreated animals. However, the compound did not lengthen the life of the mice. Similar improvements in symptoms, but not survival, have been reported for other studies with these severely ill mice, McKnight noted (see ARF related news story on Da Cruz et al., 2012; Rouaux et al., 2007).

First author Héctor De Jesús-Cortés led the PD study. He used chemical toxins to poison dopaminergic neurons in mice and the worm C. elegans. Analysis of mouse brain sections showed that A20 saved up to 60 percent of dopaminergic neurons in the substantia nigra that were killed by the toxin, MPTP, in control mice. In the nematodes, A20 saved 80 percent of the neurons normally poisoned by the toxin. A20-treated worms also moved more than their untreated counterparts. Because the drug worked similarly in mice and worms, McKnight hopes it acts on a conserved biochemical pathway that people might possess as well. However, the research is a long way from showing if that is indeed true, as treatments that work in animals have been notoriously difficult to translate to humans.

The results are exciting, said Jay Baraban of Johns Hopkins University in Baltimore, Maryland, who was not involved in the research. The big question is, What is the mechanism by which P7C3 and A20 save neurons? The team so far has not managed to recapitulate neuroprotection in vitro, Ready said, making it difficult to dissect the drugs’ targets.

P7C3’s chemical structure bears a passing resemblance to Dimebon, an antihistamine approved for use in Russia since 1983, and which has been purported to have neuroprotective effects. Dimebon reportedly looked promising in early clinical trials for Alzheimer’s, conducted in Russia (see ARF related news story), but subsequently failed to reach its endpoint in international Phase 3 trials for AD (see ARF related news story) and Huntington’s disease (see ARF related news story). De Jesús-Cortés and Tesla tested Dimebon side by side with their compounds in the PD and ALS models. Dimebon had no effect. “We gave it every chance and it does not have a lick of activity,” McKnight said. Recently, however, researchers in Samuel Gandy’s lab at Mount Sinai Medical Center, New York, reported that Dimebon was protective in models of synucleinopathy (Steele et al., 2012) and AD (see Steele et al., 2012), leading the authors to suggest that the chemical could serve as a scaffold for building more potent neuroprotective compounds. Based on the experiments the Texas researchers conducted, Ready said he believes the carbazoles are better candidates.

In addition, Ready thinks he can improve his molecules further. He would like to improve their bioavailability and reduce potential toxicity. Once satisfied with the chemical makeup, the team is interested in finding a partner for clinical studies.

In the meantime, they are seeking collaborators for more preclinical work. “It is really important for other people, not associated with us, to see if [A20] works,” McKnight said. Scientists in Miami are testing the drug in a mouse model of traumatic brain injury, and the Texas researchers are interested in sending it to Alzheimer’s researchers, too.—Amber Dance

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References

News Citations

1. Mouse Screen Yields Pro-neurogenesis Elixir 9 Jul 2010
2. Muscle Therapy Pumps Up ALS Mice, But No Survival Benefit 8 May 2012
3. AD Clinical Pipeline: Immunotherapy Woes, Dimebon Boons 18 Jul 2008
4. Dimebon Disappoints in Phase 3 Trial 4 Mar 2010
5. No Effect Seen in Huntington’s Disease Trial of Dimebon 13 Apr 2011

Paper Citations

1. Pieper AA, Xie S, Capota E, Estill SJ, Zhong J, Long JM, Becker GL, Huntington P, Goldman SE, Shen CH, Capota M, Britt JK, Kotti T, Ure K, Brat DJ, Williams NS, MacMillan KS, Naidoo J, Melito L, Hsieh J, De Brabander J, Ready JM, McKnight SL. Discovery of a proneurogenic, neuroprotective chemical. Cell. 2010 Jul 9;142(1):39-51. PubMed.
2. MacMillan KS, Naidoo J, Liang J, Melito L, Williams NS, Morlock L, Huntington PJ, Estill SJ, Longgood J, Becker GL, McKnight SL, Pieper AA, De Brabander JK, Ready JM. Development of proneurogenic, neuroprotective small molecules. J Am Chem Soc. 2011 Feb 9;133(5):1428-37. PubMed.
3. Da Cruz S, Parone PA, Lopes VS, Lillo C, McAlonis-Downes M, Lee SK, Vetto AP, Petrosyan S, Marsala M, Murphy AN, Williams DS, Spiegelman BM, Cleveland DW. Elevated PGC-1α activity sustains mitochondrial biogenesis and muscle function without extending survival in a mouse model of inherited ALS. Cell Metab. 2012 May 2;15(5):778-86. PubMed.
4. Rouaux C, Panteleeva I, René F, Gonzalez de Aguilar JL, Echaniz-Laguna A, Dupuis L, Menger Y, Boutillier AL, Loeffler JP. Sodium valproate exerts neuroprotective effects in vivo through CREB-binding protein-dependent mechanisms but does not improve survival in an amyotrophic lateral sclerosis mouse model. J Neurosci. 2007 May 23;27(21):5535-45. PubMed.
5. Steele JW, Ju S, Lachenmayer ML, Liken J, Stock A, Kim SH, Delgado LM, Alfaro IE, Bernales S, Verdile G, Bharadwaj P, Gupta V, Barr R, Friss A, Dolios G, Wang R, Ringe D, Protter AA, Martins RN, Ehrlich ME, Yue Z, Petsko GA, Gandy S. Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain. Mol Psychiatry. 2012 Aug 7; PubMed.
6. Steele JW, Lachenmayer ML, Ju S, Stock A, Liken J, Kim SH, Delgado LM, Alfaro IE, Bernales S, Verdile G, Bharadwaj P, Gupta V, Barr R, Friss A, Dolios G, Wang R, Ringe D, Fraser P, Westaway D, St George-Hyslop PH, Szabo P, Relkin NR, Buxbaum JD, Glabe CG, Protter AA, Martins RN, Ehrlich ME, Petsko GA, Yue Z, Gandy S. Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model. Mol Psychiatry. 2012 Jul 31; PubMed.

Further Reading

Papers

1. Doody RS. Dimebon as a potential therapy for Alzheimer's disease. CNS Spectr. 2009 Aug;14(8 Suppl 7):14-6; discussion 16-8. PubMed.
2. Pieper AA, Wu X, Han TW, Estill SJ, Dang Q, Wu LC, Reece-Fincanon S, Dudley CA, Richardson JA, Brat DJ, McKnight SL. The neuronal PAS domain protein 3 transcription factor controls FGF-mediated adult hippocampal neurogenesis in mice. Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):14052-7. PubMed.
3. Bachurin SO, Shevtsova EP, Kireeva EG, Oxenkrug GF, Sablin SO. Mitochondria as a target for neurotoxins and neuroprotective agents. Ann N Y Acad Sci. 2003 May;993:334-44; discussion 345-9. PubMed.
4. Moreira PI, Zhu X, Wang X, Lee HG, Nunomura A, Petersen RB, Perry G, Smith MA. Mitochondria: a therapeutic target in neurodegeneration. Biochim Biophys Acta. 2010 Jan;1802(1):212-20. PubMed.

News

1. Dimebon: Bright Star or Black Hole? 14 Oct 2009
2. Research Brief: DHA Promotes Neurogenesis, Neurite Outgrowth in Mice 29 Jun 2009
3. Muscle Therapy Pumps Up ALS Mice, But No Survival Benefit 8 May 2012
4. AD Clinical Pipeline: Immunotherapy Woes, Dimebon Boons 18 Jul 2008
5. No Effect Seen in Huntington’s Disease Trial of Dimebon 13 Apr 2011
6. Mouse Screen Yields Pro-neurogenesis Elixir 9 Jul 2010
7. Dimebon Disappoints in Phase 3 Trial 4 Mar 2010