Identification of novel 1,4-benzoxazine compounds that are protective in tissue culture and in vivo models of neurodegeneration

• Published in: Journal of neuroscience research 2010-07, Vol.88 (9), p.1970-1984
• Main Authors: Wang, Lulu, Ankati, Haribabu, Akubathini, Shashidhar Kumar, Balderamos, Michael, Storey, Chelsey A., Patel, Anish V., Price, Valerie, Kretzschmar, Doris, Biehl, Edward R., D'Mello, Santosh R.
• Format: Article
• Language: English
• Subjects: Amyloid beta-Protein Precursor - metabolism; Animals; Benzoxazines - chemistry; Benzoxazines - pharmacology; Benzoxazines - therapeutic use; Cell Death - drug effects; Cell Death - physiology; Cell Line; Cell Line, Tumor; Cerebellum - drug effects; Cerebellum - enzymology; Cerebellum - metabolism; Cerebral Cortex - drug effects; Cerebral Cortex - enzymology; Cerebral Cortex - metabolism; Disease Models, Animal; Drosophila; Humans; Huntington Disease - drug therapy; Male; Mice; Mice, Inbred C57BL; Nerve Degeneration - drug therapy; Nerve Degeneration - enzymology; Nerve Degeneration - metabolism; neurodegenerative disease; Neurodegenerative Diseases - drug therapy; Neurodegenerative Diseases - metabolism; neurons; Neurons - drug effects; Neurons - enzymology; Neurons - metabolism; neuroprotection; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Protease Nexins; Rats; Rats, Wistar; Receptors, Cell Surface - metabolism
• ISSN: 0360-4012; 1097-4547; 1097-4547
• DOI: 10.1002/jnr.22352

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 Aβ toxicity, suggesting that protection against HCA and Aβ depends on CDK inhibition. Compounds described in this study represent a novel therapeutic tool in the treatment of neurodegenerative diseases. © 2010 Wiley‐Liss, Inc.