Abstract
The number of New Zealanders living with stroke-related disabilities is increasing as our population age increases. While some spontaneous recovery occurs after stroke, most stroke patients still suffer from long-lasting impairments. The ongoing care of stroke patients results in increasing burden on healthcare resources unless new treatments are developed. Inflammation plays an important role in the pathogenesis of stroke. Many therapeutic approaches have targeted early inflammation as an attempt to reduce cell death.
Acute inflammation also plays a key role in resolving brain injury however in contrast, prolonged, uncontrolled inflammation after stroke prevents tissue repair and correlates with poor outcomes in stroke patients. Curcumin is a natural polyphenol with antioxidant and anti-inflammatory properties that has demonstrated efficacy in animal models of carcinogenesis, diabetes, wound healing, cardiomyopathy and reperfusion injury. A series of second-generation curcumin analogues (RL66) synthesised at The University of Otago have shown reduction in brain inflammation post stroke by modulating microglial phenotype. While curcumin administration prior to or immediately after stroke produces anti-inflammatory and neuroprotective effects, it is unclear whether this salvage of brain tissue translates to functional improvements and whether curcumins have a wider application as regenerative agents. The aim of this study is to extend these observations and determine whether RL66 can reduce neuroinflammation and promote functional recovery in a clinically relevant mouse model of stroke. Due to the significant gap in stroke research that exclude female animals, our group will transfer the stroke model into female animals. We also aim to validate our preclinical findings by conducting this parallel study and investigating whether sex-specific biological factors such as oestrous cycle has an impact on lesion volume of female mice.
Our findings support the results from our ex vivo studies which suggests that timeframe of administration of anti-inflammatory strategies is critical. Curcumin analogue RL66 administered within 24h did not improve functional recovery in male mice, however it remains unclear whether a higher dose of RL66 at this earlier time point could have improved short-term function. The lowest dose of RL66 (4mg/kg/day) was detrimental to survival, decreased general welfare and transiently impaired sensorimotor function iniii surviving animals. When transferring our animal model to female mice, our results indicate no relationship between oestrous stage and lesion volume.
Together these findings put emphasis on timing of anti-inflammatory interventions and dosage as important factors in the development of effective therapeutic treatments for stroke. There is potential for this work to contribute to future research which can look at implementing this therapeutic strategy in the days after stroke. If successful, this treatment approach would be available to the large population of stroke patients with late hospital admission who are not suitable for thrombolytic therapy.
Although no significant relationship is observed between oestrous cycle and lesion volume, future work is needed to confirm whether hormonal fluctuations play a role in outcomes for female mice. These findings contribute foundational knowledge that helps bridge the translational gap between animal models and clinical realities for more inclusive and effective stroke therapies in stroke care.