NP01
Identifying the Role of Lipid Metabolism in Central Nervous Systems Diseases; Is There a Common Theme for MS, ALS, Parkinson's Disease and Depression?
Neurodegenerative diseases like multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson’s Disease (PD) and depression, have a number of common pathogenic and metabolic mechanisms, which includes 1) an inflammatory component, 2) stress as a critical factor, 3) upregulated lipid metabolism, 4) high prevalence of depression. Further, humans with inherited specific carnitine palmitoyl transferase 1a (CPT1a) gene mutations have a reduced lipid metabolism and are protected from MS and depression. One key aspect in all above mentioned diseases is dysregulation of metabolism in general and alteration of lipid metabolism in particular. Studies indicate that blocking CPT1 by etomoxir and hence reversing metabolism from fatty acids to glucose is effective as treatment in animal models of MS and depression.
Objectives:
To clarify the role of CPT1 in a transgenic sod1 G93A mouse model of ALS and a toxic rotenone PD mouse model and compare this role with the effects seen in EAE and depressions animal model.
Methods:
B6.Cg-Tg(SOD1*G93A)1Gur/J mice was bought from Jackson Laboratories and maintained by mating B6.Cg-Tg(SOD1*G93A)1Gur/J male mice to female C57Bl/6J mice. Mice were weighted three times a week from day 40 and neurologically scored once a week from day 43. From day 55 motor function was assessed weekly by hangwire and rotarod test. Etomoxir and placebo treatment began at day 100. Treatment will continue until the animals reach 160 days. Glucose and ketone concentration in the urine of the mice is being measured. Afterwards, molecular biological tests as well as immunological tests will be performed.
C57Bl/6 mice will receive Rotenone oral for 28 days to induce PD after day 28 mice will be treated with etomoxir or placebo until day 60. During the experiment mice will be evaluated by different motor and sensomotor tests. Glucose and ketone concentration in the urineis being measured. Afterwards, molecular biological tests as well as immunological tests will be performed.
Results:
Both in vivo and in vitro experiments are ongoing and results will be presented at the CMSC meeting 2018.
Conclusions:
Our findings has indicated that CPT1 is a key molecule involved in lipid metabolism and that inhibition of CPT1 by etomoxir is effective in animal models of MS and depression by reversing metabolism and decreasing inflammation. Data indicate that CPT1 might also play a role in other diseases of the central nervous system such as ALS and PD.