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. 2019 Mar 7:2019:1292891.
doi: 10.1155/2019/1292891. eCollection 2019.

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

Yihang Yang  1 , Bo Pang  2 , Zihao Liu  3 , Jie Li  1 , Zhen Zhang  1 , Rui Zhang  1 , Xianzeng Hou  4 , Hua Guo  1 , Lingyi Chi  5 , Qi Pang  1 , Tao Xin  1   6
Affiliations

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

Yihang Yang et al. Oxid Med Cell Longev. .

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.

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Figures

Figure 1
Figure 1
TaClo induced motor ability impairments. (a and b) The open field test revealed that symptoms of bradykinesia in the TaClo-injected rats on the 21st and 28th days after injection compared to the control rats. ∗∗ p < 0.01 compared to the control group.
Figure 2
Figure 2
TaClo impaired the nigrostriatal system. (a) Comparison of stereotaxic coordinates in an atlas of the rat brain and the ROI assessed using DTI. Arrows pointing from A to C and from B to C show the SNc and striatum, respectively. (b) Images of the general outline of the nigrostriatal system indicate the obvious destruction of this region in the TaClo-injected rats compared to the other two groups. (c) Histogram showing a significant increase in the ADC value for the nigrostriatal system after TaClo injection. ∗ p < 0.05 compared to the control group. ∗ p < 0.05 compared to the sham group. (d) The FA value for the NP did not significantly change. (e) LFB staining showing demyelination in the SNc of the TaClo-treated rats (arrow).
Figure 3
Figure 3
TaClo decreased dopamine levels and induced a loss of TH-positive cells in the nigrostriatal system. (a and b) Western blots showing the TH levels in the nigrostriatal system on the injected and untreated side in both control and TaClo-treated rats on the 28th day. ∗∗ p < 0.01 compared to the control group. (c) Images of IF staining showing TH expression in the SNc in the two groups. (d and e) Staining for Nissl bodies in rats from two two groups. ∗∗ p < 0.01 compared to the control group. Scale bar 100 μm.
Figure 4
Figure 4
TaClo caused mitochondrial oxidative stress in the nigrostriatal system. (a) The expression of representative genes related to oxidative stress and inflammation from the GEO database (GSE7621-GPL570) was analysed. (b) ATP production was reduced after TaClo treatment. ∗∗ p < 0.01 compared to the control group. (c and d) FCM revealed an apparent increase in the MFI of ROS in the TH-positive cells from the TaClo-treated group compared to the control group. (e and f) Results of JC-1 staining in the two groups. The ratio of green and red fluorescence was increased after the TaClo treatment. ∗ p < 0.05 compared to the control group. Scale bar 100 μm.
Figure 5
Figure 5
The TaClo injection triggered inflammation in the nigrostriatal system. (a) Images of IHC staining showing significantly increased Iba-1 expression in the nigrostriatal system after the TaClo injection (400x). ∗∗ p < 0.01 compared to the control group. (b) RT-PCR results increased levels of the TNF-α, IL-6, Cox-2, and iNOS transcripts after TaClo treatment. (c and d) Cropped western blots displaying the levels of the TNF-α, IL-6, Cox-2, and iNOS proteins in the nigrostriatal system. ∗ p < 0.05 and ∗∗ p < 0.01 compared to the control group. Scale bar 100 μm.
Figure 6
Figure 6
TaClo negatively affected dopaminergic neurons. A schematic diagram showing that TaClo induces the demyelination and apoptosis of dopaminergic neurons by causing mitochondrial dysfunction and triggering the innate immune response in the nigrostriatal system.
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