|M.Sc Student||Maniv Inbal|
|Subject||The Effects of Novel TSPO Ligands on Apoptosis and the|
Potential Implications for their Use as
|Department||Department of Medicine||Supervisor||Professor Emeritus Moshe Gavish|
|Full Thesis text|
The mitochondrial 18 kDa Translocator Protein (TSPO), also known as the peripheral-type benzodiazepine receptor (PBR), is abundant in various peripheral organs and is also expressed in the CNS. In the mitochondrial membrane, TSPOs have been closely associated with the 32 kDa voltage-dependent anion channel (VDAC) and the 30-kDa adenine nucleotide transporter (ANT). VDAC and ANT are considered to form the mitochondrial permeability transition pore (MPTP). TSPO reportedly is involved in various neuropathological conditions, including neurodegenerative diseases and brain trauma. Different forms of neural injury and different neuropathological conditions such as inflammation and neurodegeneration result in the induction of TSPO expression in the nervous system including in microglia. In fact, overexpression of TSPO in reactive microglia is considered a hallmark of neurodegeneration.
We have developed novel ligands for the TSPO from four different families: quinazolines, quinoxalines, phthalazines, and PK 11195 dimers. Using the classical TSPO specific ligand, [3H]PK 11195, we determined the inhibition constant (Ki) values of our novel compounds. In vitro, using the SH-SY5Y neuroblastoma cell line, we tested the anti- apoptotic properties of our novel ligands. In vivo we tested their potential neuroprotective effects against neurodegeneration caused by systemic injections of kainic acid (KA) in rats. Compounds of the quinazoline family and PK 11195 dimers showed low Ki values in competition studies with [3H]PK 11195. Compounds of the phthalazine and quinoxaline families exhibited lower affinity. Some PK 11195 dimers exhibited pro-apoptotic effects in vitro, and may be used for further analysis regarding cancer. One of our novel TSPO ligands, MGV-9, reduced apoptosis in vitro. Another one of our novel TSPO ligands, MGV-1, reduced apoptosis in vitro and was also neuroprotective in vivo, in a dose dependent manner. Our results show that TSPO ligands can be designed specifically for anti-apoptotic and potential neuroprotective properties.