Therapeutic strategies in an animal model of neurodegeneration

Abstract

Neurodegenerative diseases have complex and multifactorial etiologies, creating an enormous burden on society without an effective treatment. This thesis utilized olfactory bulbectomized rats to investigate therapeutic approaches to neurodegenerative disorders. Removal of the olfactory bulbs, leads to widespread neurodegeneration. Olfactory bulbectomy (OBX) in rodents has been known as an animal model of depression. However, recent studies including the research presented in this thesis, suggest that OBX rodent models various aspects of neurodegenerative diseases. We have investigated the molecular and neuronal changes underlying the behavioral and cognitive decrements in lesioned animals, and from there, we have identified and validated novel therapeutic targets and strategies. The OBX-induced behavioral and cognitive impairments develop between 3 and 14 days after OBX surgery. We examined the effects of memantine, a NMDA receptor antagonist used in the treatment of Alzheimer’s disease. Early memantine administration prevented OBX-induced deficits, but post-surgical memantine administration was ineffective. Simvastatin, a cholesterol-lowering drug with putative neuroprotective properties, was also examined in OBX rats. Interestingly, simvastatin had no effect on the OBX-induced impairments but improved cognitive performance in the control animals. The role of inflammation in the OBX syndrome was investigated by administration of celecoxib, a COX-2 inhibitor, and minocycline, a microglia inhibitor. Celecoxib and minocycline partly rescued OBX-induce cognitive and behavior deficits. Furthermore, we showed that the onset of the OBX-induced cognitive changes parallel in time with signs of microglia activation in hippocampus. Considering that neurodegenerative diseases are multifactorial in origin, treatments designed to interfere at different mechanistic levels may be more effective than the traditional single-targeted pharmacological approaches. Because dietary interventions emerged as safe and effective alternative to drugs, we tested a mixture of nutritional supplements in the OBX animals. This multi-targeted diet combined contained both compounds with potential neuroprotective and neurorestorative properties. Experimental diet had a robust therapeutic effect in the OBX animals and a cognitive enhancing effect in control animals Because there is a high comorbidity between neurodegenerative disorders and gastrointestinal dysfunction, we examined effects of olfactory bulbectomy on the intestinal tract and assessed the effects of memantine, escitalopram (an antidepressant) and the multi-targeted diet. OBX leads to severe inflammation of the colon. Escitalopram and the experimental diet attenuated the OBX-induced intestinal disturbances, whereas memantine itself exacerbated intestinal dysfunction both in control and OBX animals. OBX-induced inhibition of the parasympathetic nervous system could be a plausible mechanism for OBX intestinal distress. The results of this thesis present OBX as a potential animal model for the brain-gut axis dysfunction, which may have clinical relevance for the neurodegenerative disorders. Furthermore, we have developed a multi-targeted diet, which was effective in the OBX-induced deficits and may have translational value for treating neurodegenerative disorders.