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

Aging (Albany NY). 2020 Jul 24;12(14):14897-14917. doi: 10.18632/aging.103551. Epub 2020 Jul 24.


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.

Keywords: Parkinson’s disease; adult neurogenesis; peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1α; tetramethylpyrazine derivative T-006; transcriptional factor myocyte enhancer factor 2D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Neurogenesis / physiology
  • Neuroprotection / drug effects
  • Neuroprotection / physiology
  • Neuroprotective Agents / pharmacology
  • Parkinson Disease* / metabolism
  • Parkinson Disease* / prevention & control
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism*
  • Pyrazines / pharmacology*
  • Rats
  • Signal Transduction / drug effects*
  • Treatment Outcome


  • 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