Some interesting facts about TSPO expression
FREE ACCESS: https://sci-hub.se/https://doi.org/10.1038/nrd3295
Emapunil Holds Promise as Parkinson’s Treatment, Mouse Study...
A compound called emapunil prevented the characteristic loss of nerve cells associated with Parkinson’s disease, lowered levels of dopamine, brain inflammation, and motor deficits in a mouse model of the disease. Researchers suggest that treatment with emapunil, already proven safe in humans
- TSPO is involved in the translocation of cholesterol from the outer to the inner mitochondrial membrane, which is the rate-limiting step in the synthesis of steroids and neurosteroids and one of the most well-characterized functions of this protein.
- TSPO expression seems to be a sensitive biomarker of brain damage and neurodegeneration, particularly of inflammation and reactive gliosis.
- In response to injury, TSPO expression is strongly upregulated in the peripheral nervous system in Schwann cells, macrophages and neurons. Increased TSPO ligand binding has also been investigated as a molecular in vivo sensor of neuronal damage and inflammation in patients with neurodegenerative diseases of the central nervous system (CNS) that are characterized by neuronal loss in discrete areas.
- Most of the TSPO ligands were developed primarily as neuroimaging agents and diagnostic tools for brain inflammation associated with various neuropathological conditions.
The levels of a specific protein, called translocator protein (TSPO), are elevated in microglia during inflammatory activation. TSPO ligands have been used to monitor neuroinflammation, including in patients with Parkinson’s, and have shown neuroprotective effects. However, the mechanisms through which TSPO ligands modulate inflammation are still unclear.
Mice given emapunil also showed normalized expression of genes linked to the innate immune response,
production of inflammatory molecules, and nerve cell generation and differentiation, among other processes.
Also, emapunil induced a shift from pro- to anti-inflammatory gene expression in microglia, which may underlie the compound’s protective effects, the team noted.
“This compound is able to penetrate into the microglia and flip a molecular switch that attenuates the inflammatory reaction
,” Anja Schneider, the study’s senior author, said in a press release. Emapunil, added Schneider, “has already been tested in clinical studies on humans as a possible remedy for anxiety disorders. Therefore, data on this substance exists that proves its safety and tolerability in humans.”
Unlike undesirable effects associated with conventional
benzodiazepines, AC-5216 (Emapunil) had no myorelaxant effects, did not
affect the memory (passive avoidance response) or prolong
hexobarbitone-induced sleep in mice, even at doses as high as
, p.o., although it did slightly prolong the ethanolinduced sleep time at 1000 mg/kg.
AC-5216 when repeatedly administered for two weeks does not
induce tolerance to its anxiolytic-like effects or emotional and
somatic withdrawal symptoms.
In contrast, diazepam treatment
withdrawal not only induced anxiogenic-like effects on the second
day of the withdrawal period, but also decreased body weight
gain and brought about body weight loss in mice.
STRONG TSPO BINDING!
XBD173 exerted acute anxiolytic effects, which were prevented by the TSPO antagonist PK11195, in the social exploration test and the elevated plus maze test in rats.
These preclinical studies suggest that XBD173 exerts rapid anxiolytic and antipanic effects with a more favourable side-effect profile than that of benzodiazepines
At the cellular level, the selective TSPO ligand XBD173 potentiated the amplitude and duration of GABA-mediated inhibitory postsynaptic currents in mouse medial prefrontal cortical neurons, which was prevented by finasteride. In contrast to diazepam, XBD173 did not act directly on postsynaptic GABAA receptors expressed in human WSS1 cells expressing rat α1γ2 and human β3 GABAA receptor subunits. These data provide further evidence that neurosteroidogenesis is involved in the differential effects of TSPO ligands on GABAergic neurotransmission. Neurosteroids modulate GABAA receptors via an allosteric site different from that targeted by benzodiazepines. These distinct sites of action at the GABAA receptor might explain the lack of tolerance development and withdrawal symptoms after XBD173-induced neurosteroidogenesis
I also posted here about it: