Abstract
Neurodegenerative disorders are one of the leading causes of death among the elderly. Therapeutic approaches with a single target have proven unsuccessful in treating these diseases. Structural combination of multi-functional compounds may lead to a molecule with multiple properties. In this study, we designed and synthesized T-006, a novel analog derived from two multi-functional neuroprotective chemicals, tetramethylpyrazine and J147. The methoxyphenyl group of J147 was replaced by tetramethylpyrazine. Bioactivity evaluation showed that T-006 at very low concentrations had multi-functional neuroprotective effects including rescuing iodoacetic acid-induced neuronal loss, preventing oxidative stress-induced neurotoxicity and reducing glutamate-induced excitotoxicity in vitro. Most importantly, T-006 significantly ameliorated memory impairments in APP/PS1 transgenic mice. These multiple functions of a single molecule suggest that T-006 is a promising novel neuroprotective agent for treating various neurodegenerative disorders, including and in particular Alzheimer’s disease.
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Abbreviations
- AD:
-
Alzheimer’s disease
- TMP:
-
Tetramethylpyrazine
- CGNs:
-
Cerebellar granule neurons
- PC12:
-
Pheochromocytoma cell
- DIV:
-
Days in vitro
- ROS:
-
Reactive oxygen species
- RNS:
-
Reactive nitrogen species
- IAA:
-
Iodoacetic acid
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Acknowledgments
This work was partially supported by grants from the China “12.5” Innovative Drug Project (2012ZX09103-101-055), the 2012 Hong Kong Scholars Program (122870), the China Postdoctoral Science Foundation (2012T50748 and 2013M531911), the Research Grants Council of Hong Kong (561011, 15101014), and the Hong Kong Polytechnic University (G-U952, G-YM32, G-SB10, and G-YZ15). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. We sincerely thank Ms. Josephine Leung for proofreading our manuscript.
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The authors declare no competing financial interest.
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Hai-Yun Chen and Da-Ping Xu contributed equally to this work.
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Chen, HY., Xu, DP., Tan, GL. et al. A Potent Multi-functional Neuroprotective Derivative of Tetramethylpyrazine. J Mol Neurosci 56, 977–987 (2015). https://doi.org/10.1007/s12031-015-0566-x
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DOI: https://doi.org/10.1007/s12031-015-0566-x