1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) Induces the Apoptosis of Dopaminergic Neurons via Oxidative Stress and Neuroinflammation

Abstract

Several in vitro studies have revealed the neurotoxicity of 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo). However, the underlying mechanism has not been completely elucidated, particularly in vivo. This study was designed to study the neurotoxicity of TaClo in vivo by stereotactically injecting TaClo into the striatum of Wistar rats. After the TaClo injections, rats were subjected to an open field test, and their distance travelled and tracks showed decreasing trends over time. The results of liquid chromatography-mass spectrometry analysis showed that the motor dysfunction of the TaClo-treated rats was accompanied by reduced dopamine levels in the striatum. Based on the diffusion tensor imaging data, the apparent diffusion coefficient of the nigrostriatal pathway was significantly increased, and subsequent histological staining revealed the demyelination of nigrostriatal fibres after the TaClo treatment. TaClo induced a loss of tyrosine hydroxylase-positive cells in the substantia nigra compacta. Regarding the underlying mechanism, TaClo caused oxidative stress in the nigrostriatal system by increasing the production of reactive oxygen species and reducing the mitochondria membrane potential. Meanwhile, the elevated expression of Iba-1, TNF-α, IL-6, Cox-2, and iNOS indicated microglial activation and a strong innate immune response in the nigrostriatal system. In addition, activated caspase-3 levels were increased. Thus, both mitochondrial impairments and the innate immune response are involved in TaClo-induced neurotoxicity.

In-Depth Profiling of 4-Hydroxy-2-nonenal Modification via Reversible Thiazolidine Chemistry

“…And the results (Figure S10C,D) showed that these proteins were involved in some degenerative disease pathways, such as amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease, which were associated with oxidative stress. 24 Quantification of HNE-Sensitive Sites in 293T Cells Using the SILAC-ABPP Strategy. It is reported that different sites exhibit varying sensitivities to HNE modification.…”

Mitochondrial Toxicant-Induced Neuronal Apoptosis in Parkinson’s Disease: What We Know so Far

“… 67 TCE is structurally similar to the MPTP has led to speculation that it could cause PD. 68 TaClo, one of the mitochondrial toxicants, is cytotoxic to the primary culture of dopaminergic neurons, 69 which further induces apoptosis by blocking the transfer of electrons from complex I to ubiquinone in both rat brains homogenates and liver submitochondrial particles. 70 , 71 Similarly, animal models exposed to TCE have shown nigrostriatal degeneration, which led to the mitochondrial dysfunction and the development of parkinsonian features.…”

Mitochondrial Complex I as a Pathologic and Therapeutic Target for Parkinson’s Disease

“…It inhibited MCI in the SK-N-SH neuroblastoma cell line. Stereotaxic injection of TaClo into the striatum of Wistar rats resulted in impairment of MCI and elevation of ROS . Quinolinic acid (Q) is a metabolite in the kynurenine pathway that inhibits MCI and increases ROS generation.…”

“…Stereotaxic injection of TaClo into the striatum of Wistar rats resulted in impairment of MCI and elevation of ROS. 122 Quinolinic acid (Q) is a metabolite in the kynurenine pathway that inhibits MCI and increases ROS generation. It was also found to promote oligomerization of Tau.…”