Date of Award
Master of Science (MS)
Sandra J. Hewett
3-Nitropropionic Acid, Huntington's Disease, Interleukin-1, Neurodegeneration, Oxidative Stress, Striatal Injury
Interleukin-1β (IL-1β), classically considered as a pro-inflammatory cytokine, has proven essential to cellular defense in nearly all tissues (Kaur et al., 2014, Ren and Torres, 2009). In brain, studies suggest that IL-1β has pleiotrophic effects. It acts as a neuromodulator, has been implicated in the pathogenic processes associated with a number of CNS diseases, but has also been shown to provide protection to the injured CNS. With respect to the latter, IL-1β signalling appears to mitigate pathology and motor symptoms in a mouse model of Huntington’s disease (HD), a progressive neurodegenerative condition that targets the striatum. Specifically, HD mice bred onto an IL-1R1 null background demonstrate greater pathological striatal HTT aggregation that coincides with increased severity of motor symptoms (Wang et al., 2010). Of interest for this thesis, mitochondrial dysfunction and subsequent reactive oxygen species (ROS) generation appear to precipitate neuropathology in HD (Emerit et al., 2004). Also of interest, is research from this laboratory demonstrating that IL-1β can protect neural cells against oxidant-induced injury (He et al., 2015) (Chowdhury, unpublished observations). Thus, in this thesis, I explored whether IL-1β signalling could protect against oxidative stress-generated brain damage in vivo by employing a chemical model of HD. Toward this end, both male and female mice (16-18 wks) that were either null or wild-type for the IL-1β signalling receptor, IL-1R1, were treated systemically with 3-nitropropionic acid (3-NP), a phyto/fungal mitochondrial toxin (Pedraza-Chaverrí et al., 2009), for a total cumulative dose of 920mg/kg. Comparisons of the histological striatal injury and extent of behavioral symptomatology were made. Motor symptoms —including reduced general locomotor activity, hind limb and truncal dystonia, and postural instability —increased progressively with increasing days of dosage with 3-NP, in both sexes regardless of genotype, demonstrating no observable difference in response during treatment. Despite this, histological analysis of the striatum, measured over seven levels ranging from +1.22 to -0.18 from bregma, revealed that IL-1R1 null male, but not female, mice had a greater incidence of striatal lesions that were also larger in size compared to their wild-type littermate controls. These results indicate that endogenous IL-1β signalling mitigated 3-NP induced structural, but not functional, striatal injury in male but not female mice.
Allen, Matthew Frederick, "INCREASED STRIATAL VULNERABILITY TO 3-NITROPROPIONIC ACID IN MALE, BUT NOT FEMALE, MICE LACKING INTERLEUKIN-1R1" (2017). Theses - ALL. 190.