The Novel Tetramethylpyrazine Bis-nitrone (TN-2) Protects Against MPTP/MPP+-Induced Neurotoxicity via Inhibition of Mitochondrial-Dependent Apoptosis

Abstract

Mitochondrial-dependent apoptosis plays an important role in the degeneration of dopaminergic neurons in Parkinson's disease (PD). Methyl-4-phenyl-1,2,3,6-tetra- hydropyridine (MPTP), the most widely used neurotoxin to simulate PD, is converted to 1-methyl-4-phenylpyridinium (MPP(+)) in vivo. MPP(+) induces excessive intracellular reactive oxygen species (ROS), leading to mitochondrial-dependent apoptosis via sequentially opening mitochondria permeability transition pore (mPTP) to release cytochrome c from mitochondria into cytoplasm and activate pro-apoptotic caspase proteins. We have previously synthesized 2,5-[[(1,1-dimethylethyl)oxidoimino]methyl]-3,6-trimethylpyrazine (TN-2), a novel derivative of the Chinese herb medicine tetramethylpyrazine (TMP). TN-2 is armed with two powerful free radical-scavenging nitrone moieties. TN-2 significantly reversed the loss of dopaminergic neurons in the substantia nigra and the decrease in dopamine level in the striatum induced by MPTP in mice. TN-2 ameliorated the MPTP-induced decrease of brain superoxide dismutase activity and glutathione concentration and increase of brain malondialdehyde. In addition, TN-2 inhibited MPP(+)-induced neuronal damage/apoptosis in primary cerebellum granular neurons (CGNs) and SH-SY5Y cells. TN-2 decreased excessive intracellular ROS, prevented the loss of mitochondrial membrane potential, blocked the release of mitochondrial cytochrome c and inhibited the activation of caspase-3 and caspase-9. Moreover, TN-2 treatment increased the mRNA expression of mitochondrial biogenesis factors peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1 (PGC- 1α and β) and mitochondrial transcription factor A (Tfam) in SH-SY5Y cells and CGNs. These results suggest that TN-2 protects dopaminergic neurons against MPTP/MPP(+)-induced neurotoxicity via the inhibition of mitochondrial-dependent apoptosis and possibly via the activation of mitochondrial biogenesis, indicating that TN-2 is a potential new treatment for PD.

RETRACTED ARTICLE: TN-2 Ameliorates Tunicamycin-Induced Mitochondria and Endoplasmic Reticulum Stress-Associated Apoptosis in Rat Dorsal Root Ganglion Neurons

“…1b). TN-2 was armed with two powerful free radical-scavenging nitrone moieties and showed remarkable activity protecting neuronal cells from oxidative injury in vitro (Xu et al 2014a) and ischemic stroke injury (Sun et al 2012) and also neurodegenerative diseases in animal models (Xu et al 2014c).…”

RETRACTED ARTICLE: TN-2 modulates LPS-induced inflammatory response in human renal tubular epithelial cells by blocking TLR4-mediated NF-κB activation via MyD88- and TRIF-dependent mechanism

“…We purchased LPS from Sigma-Aldrich Co (St. Louis, MO). The choice of TN-2 concentrations was based on previous studies [16][17][18][19] and the present study of MTT assay.…”

“…Recent studies have showed that TN-2 protected neuronal cells from 6-OHDA-or MPTP/MPP ? -induced neurotoxicity and NF-jB-mediated neuro-inflammation [16][17][18][19]. Despite evidence indicating the neuroprotective effect of TN-2, there is a lack of data describing the role of TN-2 in intrarenal inflammation.…”

Discovery of novel anti-parkinsonian effect of schisantherin A in in vitro and in vivo

“…Brain tissue fixation, paraffin embedding, sectioning and immunohistochemistry with antibody against TH were performed as described in our previous publications [21,22]. The results were analyzed by counting the numbers of TH-positive cells at ×10 magnifications on a stereomicroscope (BX51, Olympus Corp., Japan).…”