Neuroprotective and neurogenic effects of novel tetramethylpyrazine derivative T-006 in Parkinson's disease models through activating the MEF2-PGC1α and BDNF/CREB pathways.

Abstract

T-006, a new derivative of tetramethylpyrazine, has been recently found to protect against 6-hydroxydopamine (6-OHDA)-induced neuronal damage and clear α-synuclein (α-syn) by enhancing proteasome activity in an α-syn transgenic Parkinson's disease (PD) model. The effect of T-006 on the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD model, however, has not been tested and T-006's neuroprotective mechanisms have not been fully elucidated. In this study, we further investigated the neuroprotective and neurogenic effects of T-006 and explored its underlying mechanism of action in both cellular and animal PD models. T-006 was able to improve locomotor behavior, increase survival of nigra dopaminergic neurons and boost striatal dopamine levels in both MPTP- and 6-OHDA-induced animals. T-006 treatment restored the altered expressions of myocyte enhancer factor 2D (MEF2D), peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1α (PGC1α) and NF-E2-related factor 1/2 (Nrf1/2) via modulation of Akt/GSK3β signaling. T-006 stimulated MEF2, PGC1α and Nrf2 transcriptional activities, inducing Nrf2 nuclear localization. Interestingly, T-006 promoted endogenous adult neurogenesis toward a dopaminergic phenotype by activating brain-derived neurotrophic factor (BDNF) and cAMP responsive element-binding protein (CREB) in 6-OHDA rats. Our work demonstrated that T-006 is a potent neuroprotective and neuroregenerative agent that may have therapeutic potential in the treatment of PD.

• Authors: Haiyun Chen, Jie Cao, Ling Zha, Peile Wang, Zheng Liu, Baojian Guo, Gaoxiao Zhang, Yewei Sun, Zaijun Zhang, Yuqiang Wang
• Journal: Aging (Aging (Albany NY)) Vol. 12 Issue 14 Pg. 14897-14917 (07 24 2020) ISSN: 1945-4589 [Electronic] United States
• PMID: 32710729 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Brain-Derived Neurotrophic Factor
• Cyclic AMP Response Element-Binding Protein
• Hydrazones
• MEF2 Transcription Factors
• Neuroprotective Agents
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Pyrazines
• T-006 compound

Topics

• Animals
• Brain-Derived Neurotrophic Factor (metabolism)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Disease Models, Animal
• Hydrazones (pharmacology)
• MEF2 Transcription Factors (metabolism)
• Mice
• Neurogenesis (drug effects, physiology)
• Neuroprotection (drug effects, physiology)
• Neuroprotective Agents (pharmacology)
• Parkinson Disease (metabolism, prevention & control)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (metabolism)
• Pyrazines (pharmacology)
• Rats
• Signal Transduction (drug effects)
• Treatment Outcome