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

Lulu Wang, Haribabu Ankati, Shashidhar Kumar Akubathini, Michael Balderamos, Chelsey A. Storey, Anish V. Patel, Valerie Price, Doris Kretzschmar, Edward R. Biehl, Santosh R. D'Mello

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1970-1984
Number of pages15
JournalJournal of Neuroscience Research
Volume88
Issue number9
DOIs
StatePublished - Jul 2010

Fingerprint

Benzoxazines
Cyclin-Dependent Kinases
Neurons
Huntington Disease
p38 Mitogen-Activated Protein Kinases
Neurodegenerative Diseases
Corpus Striatum
Calcium-Calmodulin-Dependent Protein Kinases
Histone Deacetylases
Amyloid beta-Protein Precursor
Mitogen-Activated Protein Kinase Kinases
Cyclic AMP-Dependent Protein Kinases
Phosphatidylinositol 3-Kinases
Drosophila
Parkinson Disease
6-amino-2-(3',5'-dibromo-4'-hydroxybenzylidene)-2H-benzo(b)(1,4)oxazin-3-(4H)-one
Potassium
Alzheimer Disease
Phosphotransferases
Stroke

Keywords

  • Neurodegenerative disease
  • Neurons
  • Neuroprotection

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Wang, L., Ankati, H., Akubathini, S. K., Balderamos, M., Storey, C. A., Patel, A. V., ... D'Mello, S. R. (2010). Identification of novel 1,4-benzoxazine compounds that are protective in tissue culture and in vivo models of neurodegeneration. Journal of Neuroscience Research, 88(9), 1970-1984. https://doi.org/10.1002/jnr.22352

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

In: Journal of Neuroscience Research, Vol. 88, No. 9, 07.2010, p. 1970-1984.

Research output: Contribution to journalArticle

Wang, L, Ankati, H, Akubathini, SK, Balderamos, M, Storey, CA, Patel, AV, Price, V, Kretzschmar, D, Biehl, ER & D'Mello, SR 2010, 'Identification of novel 1,4-benzoxazine compounds that are protective in tissue culture and in vivo models of neurodegeneration', Journal of Neuroscience Research, vol. 88, no. 9, pp. 1970-1984. https://doi.org/10.1002/jnr.22352
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. / Identification of novel 1,4-benzoxazine compounds that are protective in tissue culture and in vivo models of neurodegeneration. In: Journal of Neuroscience Research. 2010 ; Vol. 88, No. 9. pp. 1970-1984.
@article{99004579a5ab4130b1a574b4eb7fbf03,
title = "Identification of novel 1,4-benzoxazine compounds that are protective in tissue culture and in vivo models of neurodegeneration",
abstract = "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.",
keywords = "Neurodegenerative disease, Neurons, Neuroprotection",
author = "Lulu Wang and Haribabu Ankati and Akubathini, {Shashidhar Kumar} and Michael Balderamos and Storey, {Chelsey A.} and Patel, {Anish V.} and Valerie Price and Doris Kretzschmar and Biehl, {Edward R.} and D'Mello, {Santosh R.}",
year = "2010",
month = "7",
doi = "10.1002/jnr.22352",
language = "English (US)",
volume = "88",
pages = "1970--1984",
journal = "Journal of Neuroscience Research",
issn = "0360-4012",
publisher = "Wiley-Liss Inc.",
number = "9",

}

TY - JOUR

T1 - Identification of novel 1,4-benzoxazine compounds that are protective in tissue culture and in vivo models of neurodegeneration

AU - Wang, Lulu

AU - Ankati, Haribabu

AU - Akubathini, Shashidhar Kumar

AU - Balderamos, Michael

AU - Storey, Chelsey A.

AU - Patel, Anish V.

AU - Price, Valerie

AU - Kretzschmar, Doris

AU - Biehl, Edward R.

AU - D'Mello, Santosh R.

PY - 2010/7

Y1 - 2010/7

N2 - 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.

AB - 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.

KW - Neurodegenerative disease

KW - Neurons

KW - Neuroprotection

UR - http://www.scopus.com/inward/record.url?scp=77953532181&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953532181&partnerID=8YFLogxK

U2 - 10.1002/jnr.22352

DO - 10.1002/jnr.22352

M3 - Article

C2 - 20143421

AN - SCOPUS:77953532181

VL - 88

SP - 1970

EP - 1984

JO - Journal of Neuroscience Research

JF - Journal of Neuroscience Research

SN - 0360-4012

IS - 9

ER -