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.Nootropics Powder
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. However, to date, the exact aetiology and underlying molecular mechanisms of PD remain largely unclear [1]. 1-Methy-
l-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is known to cause PD. 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]. Trichloroethylene (TCE) is widely used as a detergent, extractant, and solvent. The main
routes of TCE exposure are industrial waste gas, contaminated groundwater, and volatile organic solvents. 1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) is an in
vivo metabolic product of TCE. TaClo belongs to the β-carboline family and has a structure similar to the synthetic neurotoxin 1-methyl-4-phenylpyridinium iodide (MPP+) [3].
Previous studies have reported TaClo concentrations ranging from less than 1 ng to 35 ng per millilitre in blood samples from patients who were orally treated with chloral hydrate
for 3 days to 6 months [4, 5]. Moreover, TaClo is approximately 10 times more potent than MPTP [6], and it penetrates the blood-brain barrier more easily than MPTP [7].
However, to date, the mechanism by which TaClo induces PD remains unclear.
The nigrostriatal pathway (NP) is an anatomical circuit comprising dopaminergic neurons that project from the substantia nigra compacta (SNc) to the striatum forming part of the
basal ganglia motor loop. Dopaminergic neurons in the SNc and their terminals in the striatum constitute the nigrostriatal dopaminergic system. This system is easily impaired
because many extracellular materials can be taken up via plasma membrane dopamine transporters [8]. We hypothesized that TaClo causes PD symptoms by damaging the
nigrostriatal system. Mitochondrial dysfunction, oxidative stress, and inflammation are involved in degenerative diseases [9]. As shown in the study by Prof. Bing G., TCE treatment
impairs mitochondrial complex I activity [10]. Furthermore, by referring to the GEO database (GSE7621-GPL570), which provides analyses of the SNc in postmortem brain tissues
from patients, the expression of the Cox-2, iNOS, GABPA, and Keap 1 genes is upregulated in patients with PD. We also hypothesized that TaClo induces a positive feedback loop
between mitochondrial oxidative stress and the innate immune response in the central nervous system (CNS). Mitochondrial inhibitors, such as rotenone and MPTP, are known to
increase reactive oxygen species (ROS) production by blocking the electron transport chain at a particular site [11], further causing abnormalities in neuroglia [12]. More
importantly, substantially elevated ROS levels are implicated in the activation of the innate immune response [13]. Subsequently, activated microglia release ROS, further
impairing the mitochondria. This type of positive feedback between mitochondrial dysfunction and the inflammatory cascade in the brain may cause secondary injury, such as
demyelination, dopaminergic neuron apoptosis, and neurodegenerative diseases.