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.
Highlights
Parkinson’s disease (PD) is one of the most common neurodegenerative movement disorders and affects approximately 1-2% of elderly people
In the TaClo group, the distance travelled in the open field test showed an evident decreasing trend over time
Rats in the control group did not show any significant difference in the distance travelled at different time points (p > 0 05)
Summary
Parkinson’s disease (PD) is one of the most common neurodegenerative movement disorders and affects approximately 1-2% of elderly people. Both genetic and environmental factors are strongly correlated with the development of PD. To date, the exact aetiology and underlying molecular mechanisms of PD remain largely unclear [1]. Many other structural analogues of MPTP have been discovered in the environment, including herbicides (e.g., paraquat), alkaloids (e.g., 1,2,3,4-tetrahydroisoquinolines), and β-carbolines [2]. 1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) is an in vivo metabolic product of TCE. TaClo belongs to Oxidative Medicine and Cellular Longevity the β-carboline family and has a structure similar to the synthetic neurotoxin 1-methyl-4-phenylpyridinium iodide (MPP+) [3]. To date, the mechanism by which TaClo induces PD remains unclear
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