|M.Sc Student||Oren May Meirav|
|Subject||Neuroprotection by the Novel Iron Chelator,|
M30, in Neurodegeneration Model Induced by Kainic
|Department||Department of Medicine||Supervisor||Professor Emeritus Moussa Youdim|
There is evidence that increased iron ion is involved in the mechanisms that underlie a number of neurodegenerative diseases such as: Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's chorea and amyotrophic lateral sclerosis (ALS), along with apoptotic cell death and inflammation. Thus, metal chelation could be considered a rational therapeutic strategy for these disorders. The present investigation was carried out to elucidate the potential neuroprotective activity of M30 in the Kainic acid (KA) model of hippocampal neurodegeneration. M30 is a multifunctional compound, combining the neuroprotective effects of the N-propargylamine moiety of the novel anti-parkinsonian drug, rasagiline, with the iron chelating activity of VK-28. First, focus was placed on the expression of two major iron metabolism-regulatory proteins, divalent metal transporter-1 (DMT1) and transferrin receptor (TfR) in response to KA intoxication using histopathology and western blot analyses. The untreated hippocampus was lightly stained for DMT1, while a substantial immunoreaction appeared in the degenerating Cornu Ammonis (CA) 3-1 fields, after KA lesion. An opposite picture was observed with TfR, where the strong labeling of hippocampal CA1-3 neurons was dramatically decreased by KA. Administration of M30 (10 mg/kg per day, orally) for 5 consecutive days significantly attenuated the effect of KA on both proteins. The involvement of apoptotic processes and inflammation as major contributors to KA neurotoxicity has been suggested previously. Indeed, the expression of Bcl-2, one of the main anti-apoptotic, mitochondrial acting mediators, was found to be negatively affected by KA in hippocampal pyramidal neurons. M30 was able to prevent this decline when given before KA, and the levels approximated those of saline-treated controls. On the other hand, a strong immunoreactivity was observed in the inflammation mediators, interleukin 1b (IL-1band glial fibrilliary acidic protein (GFAP) in the hippocampus of mice after excitotoxic injury by KA. Furthermore, recent studies have shown that cellular iron levels alter amyloid precursor protein (APP) protein and/ or change the amount of soluble APP secreted into the conditioned medium of iron-treated cells. In our hands, pharmacological manipulation of the iron pool level by M30 chelation resulted in a significant suppression of APP protein. Another multifunctional derivative of VK28, HLA20, showed similar results. This study provides further support for a crucial role that the neuroprotective iron chelator, M30, plays in preventing detrimental effects in the degenerating hippocampus, indicating a further implication to iron-associated neurodegenerative disorders therapy.