Researchers from Southern Methodist University and the University of Texas at Dallas have collaborated to develop new benzoxazine compounds to prevent neurodegeneration. Similar indolone compounds had been found to inhibit cell death but were toxic at higher concentrations. The benzoxazine compounds were synthesized by altering the ring core structure, preventing toxicity even at high doses. Benzoxazines are the reaction products of an amine, a phenol and formaldehyde.
The researchers tested one of these compounds, HSB-13, in a toxin model of HD where mice are administered 3-nitroproprionic acid (3-NP), a neurotoxin which causes striatal cell death. 3-NP causes an acute injury rather than the slow degeneration seen in HD; this model was widely used prior to the development of genetic models. Mice pre-treated with HSB-13 had fewer striatal lesions and improved motor performance. In addition, mouse neuroblastoma cells were treated with homocysteic acid to induce oxidative stress-mediated apoptosis; the cells that were pre-treated with HSB-13 survived. In another experiment, HSB-13 increased survival time in an Alzheimer's fruitfly model.
"Our compounds protect against neurodegeneration in mice," said synthetic
organic chemist Edward R. Biehl, the Department of Chemistry professor who led development of the compounds at SMU. "Given successful development of the compounds into drug therapies, they would serve as an effective treatment for patients with degenerative brain diseases."
"Additional research needs to be done, but these compounds have the potential for stopping or slowing the relentless loss of brain cells in diseases such as Alzheimer's and Parkinson's," said collaborator Santosh D'Mello, professor of molecular and cell biology who led the team at UT Dallas. "The protective effect that they display in tissue culture and animal models of neurodegenerative disease provides strong evidence of their promise as drugs to treat neurodegenerative disorders."
Dallas-based startup EncephRx, Inc. was granted the worldwide license to the jointly owned compounds. A biotechnology and therapeutics company, EncephRx will develop drug therapies based on the new class of compounds as a pharmaceutical for preventing nerve-cell damage, delaying onset of degenerative nerve disease and improving symptoms.
Aaron Heifetz, president and chief executive officer of EncephRx, Inc., said, "We believe this library of novel neuroprotective compounds will prove an important step in the effort to improve the health for patients with neurodegenerative diseases, such as Huntington's disease, Alzheimer's disease and Parkinson's disease." EncephRx initially will focus its development and testing efforts toward Huntington's disease and potentially will have medications ready for human trials in two years, said Heifetz.
Chris Jeffers, managing partner of FirstStage Bioventures, the parent company of EncephRx, added, "FirstStage is very excited about this technology and looks forward to helping EncephRx quickly move these compounds into the clinic."
Southern Methodist University press release, December 7, 2010.
Texas University at Dallas press release, December 10, 2010.
Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease and conditions such as ischemic stroke affect millions of individuals annually and exert an enormous financial burden on society. A hallmark of these conditions is the abnormal loss of neurons. Currently, there are no effective strategies to prevent neuronal death in these pathologies. We report that several 2-arylidine and 2-hetarylidin derivatives of the 1,4-benzoxazines class of compounds are highly protective in tissue culture models of neurodegeneration. Results obtained using pharmcalogical inhibitors indicate that neuroprotection by these compounds does not involve the Raf-MEK-ERK or PI-3 kinase-Akt signaling pathways nor other survival-promoting molecules such as protein kinase A (PKA), calcium calmodulin kinase A (CaMK), and histone deacetylases (HDACs). We tested one of these compounds, (Z)-6-amino-2-(3',5'-dibromo-4'-hydroxybenzylidene)-2H-benzo[b][1,4]oxazin-3(4H)-one, designated as HSB-13, in the 3-nitropropionic acid (3-NP)-induced mouse model of Huntington's disease. HSB-13 reduced striatal degeneration and improved behavioral performance in mice administered with 3-NP. Furthermore, HSB-13 was protective in a Drosophila model of amyloid precursor protein (APP) toxicity. To understand how HSB-13 and other 1,4-benzoxazines protect neurons, we performed kinase profiling analyses. These analyses showed that HSB-13 inhibits GSK3, p38 MAPK, and cyclin-dependent kinases (CDKs). In comparison, another compound, called ASK-2a, that protects cerebellar granule neurons against low-potassium-induced death inhibits GSK3 and p38 MAPK but not CDKs. Despite its structural similarity to HSB-13, however, ASK-2a is incapable of protecting cortical neurons and HT22 cells against homocysteic acid (HCA)-induced or Abeta toxicity, suggesting that protection against HCA and Abeta depends on CDK inhibition. Compounds described in this study represent a novel therapeutic tool in the treatment of neurodegenerative diseases.