This Is AuburnElectronic Theses and Dissertations

Neuroprotective effects of carnitinoid antioxidants in rodent models of mitochondrial dysfunction




Hoffman, Michelle

Type of Degree

Master's Thesis


General Veterinary Medicine


The pathological effects of mitochondrial dysfunction result from both oxidative damage and bioenergetic deficiency, and are more severe in cells and tissues with high metabolic energy demands such as neurons, skeletal muscle and cardiac muscle. In this context, our research efforts have focused on a group of proprietary synthetic lipoylcarnitine and butyrylcarnitine derivatives (PMX compounds) as potential therapies to minimize oxidative damage and maximize mitochondrial energy production in animal models of mitochondrial disease. The rotenone-induced rat model of Parkinson’s disease (PD) was selected for its established inhibition/disruption of mitochondrial complex I leading to PD-like symptoms including bradykinesia, postural instability, and/or rigidity. By applying a broad spectrum battery of neuromotor tests our goal was to correlate quantifiable neuromotor performance to neuronal lesioning seen in the substantia nigra pars compacta (SNpc) of this model, creating an informative preclinical evaluation of potential therapeutic compounds. Tyrosine hydroxylase immunolabeling of SNpc from rotenone treated rats showed decreased dopaminergic neuronal population co-administration using PMX-500FI (lipoylcarnitine) or PMX-550DBr (butyrylcarnitine) protected against loss of tyrosine hydroxylase immunorecative neurons in the SNpc. Additionally, similar experiments were performed with the transgenic PARK2 mouse, a model of autosomal-recessive juvenile PD selected for its parkin protein deficiency. These mice display PD-like symptoms due to disruption of mitochondrial recycling, which allows dysfunctional mitochondria to remain. We further challenged these mice with rotenone in hopes of creating a more robust mouse model to evaluate the therapeutic effect of antioxidant compounds.