|Ph.D Student||Shehadeh Mona|
|Subject||Mitochondrial Involvement in Traumatic Brain Injury|
|Department||Department of Medicine||Supervisors||Dr. Jean Francois Soustiel|
|Professor Emeritus Moshe Feinsod|
|Dr. Eilam Palzur|
|Full Thesis text|
Traumatic Brain Injury (TBI) is the lead?ing cause of death and disability for people under the age of 45 years. Many survivors live with significant disabilities, resulting in major socioeconomic burden as well.
TBI can be divided into primary injury, the immediate and irreversible damage results by the initial impact; and secondary injury, a delayed response that results from a complex group of cellular and molecular responses to the primary injury characterized by delayed cell death. While much has been learned about the molecular and cellular mechanisms of TBI, translation into clinical trial was not successful; accordingly, no significant improvement of treatment was achieved.
During the past decade, disruption of mitochondrial function and structural integrity has emerged as a pivotal event in the generation of secondary cell damage after TBI, due to pathological molecular events that are integrated at the mitochondrial level, resulting in the induction of the mitochondrial permeability transition pore (mPTP) and eventually cell death.
The exact structure of the mPTP is not yet fully clarified, several critical components have been identified, in particular the 32-kDa voltage-dependent anion channel (VDAC) and the 30-kDa adenine nucleotide translocator (ANT). Another component of the mPTP is represented by the 18 kDa translocator protein (TSPO), at its outer mitochondrial membrane location; the TSPO is closely related to the VDAC and to the ANT, suggesting that it may be involved with the control of the mPTP and the apoptotic process, supporting this, several studies showed modulation apoptosis mediated by TSPO ligands in malignant cell lines. In our laboratory we have shown that TSPO expression correlated with the number of apoptotic cells in the injured tissue, suggesting that modulation of TSPO by specific ligands may affect the destiny of injured neuron.
Etifoxine is a clinically available anxiolytic drug and TSPO ligand and has been demonstrated to serve multiple functions in nervous system. No studies have yet been conducted in TBI following treatment with etifoxine. Therefore we hypothesized that etifoxine treatment can reduce mitochondrial damage and thus minimize secondary brain injury probably by modulating TSPO activity to prevent the opening of the mPTP following TBI.
To analyze the potential neuroprotective effect of etifoxine treatment following TBI we employed the marmarou weight drop model, and assessed its effect on apoptosis, neuronal survival and astrocytes activation by immunohistochemistry. For the identification of mitochondrial membrane permeabilization, we measured the mitochondrial transmembrane potential; Ca2 induced mitochondrial swelling and cytochrome c release. Finally, we performed behavioral tests and lesion volume assessment by cresyl violet staining.
The neuroprotective effects of etifoxine included increased neuronal survival, decreased cell death and decreased astroglial activation; these coincide with the suppression of Ca2 induced mitochondrial swelling and the energy failure restoration. No significant changes in cytochrome c release were observed. Etifoxine administration was also beneficial for improving neurological function and decreasing lesion volume after TBI.
Targeting mitochondrial membrane permeabilization by etifoxine provided an excellent therapeutic window for the treatment of TBI in rats. Etifoxine may also be used as a pilot for the development of new TSPO ligands for neuroprotection.