Neonatal hypoxic-ischaemic encephalopathy (HIE) is major cause of neonatal mortality and morbidity. Therapeutic hypothermia is standard clinical care for moderate hypoxic-ischaemic (HI) brain injury, however it reduces the risk of death and disability only by 11% and 40% of the treated infants still develop disabilities. Thus it is necessary to develop supplementary therapies to complement therapeutic hypothermia in the treatment of neonatal HIE. The modified Rice-Vannucci model of HI in the neonatal mouse is well developed and widely applied with different periods of hypothermia used as neuroprotective strategy in combination with other agents. However, different studies use different periods, time of initiation and duration of hypothermia following HI, with subsequent varying degrees of neuroprotection. So far most rodent data is obtained using exposure to 5-6h of therapeutic hypothermia. Our aim was to compare the effect of exposure to three different short periods of hypothermia (1h, 1.5h and 2h) following HI insult in the postnatal day 7 C57/Bl6 mouse, and to determine the shortest period providing neuroprotection. Our data suggests that 1h and 1.5h of hypothermia delayed by 20min following a 60min exposure to 8%O2 do not prove neuroprotective. However, 2h of hypothermia significantly reduced tissue loss, TUNEL+ cell death and microglia and astroglia activation. We also observed improved functional outcome 7 days after HI. We suggest that the minimal period of cooling necessary to provide moderate short term neuroprotection and appropriate for the development and testing of combined treatment is 2h.

Hypoxic-ischemic encephalopathy (HIE) is a major cause of mortality and morbidity in neonates, with an estimated global incidence of 3/1,000 live births. HIE brain damage is associated with an inflammatory response and oxidative stress, resulting in the activation of cell death pathways. At present, therapeutic hypothermia is the only clinically approved treatment available for HIE. This approach, however, is only partially effective. Therefore, there is an unmet clinical need for the development of novel therapeutic interventions for the treatment of HIE. Curcumin is an antioxidant reactive oxygen species scavenger, with reported anti-tumor and anti-inflammatory activity. Curcumin has been shown to attenuate mitochondrial dysfunction, stabilize the cell membrane, stimulate proliferation, and reduce injury severity in adult models of spinal cord injury, cancer, and cardiovascular disease. The role of curcumin in neonatal HIE has not been widely studied due to its low bioavailability and limited aqueous solubility. The aim of this study was to investigate the effect of curcumin treatment in neonatal HIE, including time of administration and dose-dependent effects. Our results indicate that curcumin administration prior to HIE in neonatal mice elevated cell and tissue loss, as well as glial activation compared to HI alone. However, immediate post-treatment with curcumin was significantly neuroprotective, reducing grey and white matter tissue loss, TUNEL+ cell death, microglia activation, reactive astrogliosis, and iNOS oxidative stress when compared to vehicle-treated littermates. This effect was dose-dependent, with 200 μg/g body weight as the optimal dose-regimen, and was maintained when curcumin treatment was delayed by 60 or 120 min post-HI. Cell proliferation measurements showed no changes between curcumin and HI alone, suggesting that the protective effects of curcumin on the neonatal brain following HI are most likely due to curcumin’s anti-inflammatory and antioxidant properties, as seen in the reduced glial and iNOS activity. In conclusion, this study suggests curcumin as a potent neuroprotective agent with potential for the treatment of HIE. The delayed application of curcumin further increases its clinical relevance.

IntroductionSporadic inclusion body myositis (sIBM) is the most common muscle disease affecting older adults with no disease-modifying treatment. Resistance exercises increase muscle hypertrophy, but weakness prevents exercising with higher resistance. In healthy subjects, augmentation of light-load training with blood flow restriction improved muscle strength1; and similar exercises were safe in the elderly.2 We therefore investigate whether resistance exercises with blood flow restriction is safe and helpful in sIBM patients. We explored methods for exercising weak leg muscles, and options for better outcome measures.MethodsA matched-control pilot study, with 12-week treatment and 4-week follow-up periods, where participants concentrated on lower limbs resistance exercises with 50% blood flow restriction 3 times/week, at 20%-30% of their repetition maximum. Patients are reviewed 4-weekly for muscle strength, blood biomarkers, 2-minute walk test (2MWT), timed up-and-go (TUG) test, minimal chair height standing ability test (MCHSAT), thigh girths, and quality of life scales.Results4 patients with varying abilities were on the exercise arm, and 3 acted as controls. Muscle groups with MRC score ≥2 were able to be exercised. We found strength testing by hand-held dynamometer was unreliable, whereas the 2MWT, TUG test and MCHSAT showed less variability. All patients could perform their exercises at significantly increased repetitions or weights by week 4, without concerning adverse events, with trend towards continued improvement over the 4-month period.ConclusionResistance exercises with blood flow restriction appear safe, and may be helpful in sIBM patients, even in weakened muscles, enabling improvement in muscle strength and endurance.ReferencesHughes L, Paton B, Rosenblatt B, Gissane C, Patterson SD. Blood flow restriction training in clinical musculoskeletal rehabilitation: a systematic review and meta-analysis. Br J Sports 2017.Vechin FC, Libardi CA, Conceicao MS, et al. Comparisons between low-intensity resistance training with blood flow restriction and high-intensity resistance training on quadriceps muscle mass and strength in elderly. J Strength Cond Res 2015.

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