Curcumin: Novel Treatment in Neonatal Hypoxic-Ischemic Brain Injury

Abstract

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.

Curcumin Loaded Polymeric vs. Lipid Nanoparticles: Antioxidant Effect on Normal and Hypoxic Olfactory Ensheathing Cells

“…Accordingly, in the study of Ferreira et al, the authors found a dose-dependent neuroprotection provided by immediate and delayed treatment with Cur following neonatal hypoxic-ischemic brain injury. The precise mechanism of this protection is unclear; however, their results showed effects of Cur on oxidative stress and myelination, inflammation and transcription (STAT3 Y705) and mitochondrial dysfunction (STAT3 S727 and PHB) [ 55 ]. Considering this, cells cultured under hypoxic conditions can be used as a valid in vitro model in order to evaluate the anti-ROS properties of active molecules such as Cur.…”

From Preclinical Stroke Models to Humans: Polyphenols in the Prevention and Treatment of Stroke

“…Curcumin possesses several beneficial properties that could make it a suitable candidate for stroke prevention or treatment, including anti-inflammatory, antilipemic, antiaggregant, neuroprotective and epigenetic modulatory activities [ 275 ]. Pre- and posthypoxia treatment with curcumin was found to effectively promote neuroprotection in rat neurons challenged with OGD [ 276 ], in neonatal mice subjected to hypoxic–ischemic brain injury [ 277 ], in MCAO rodents [ 278 , 279 , 280 , 281 , 282 , 283 , 284 ] and in stroke-prone spontaneously hypertensive rats [ 285 ].…”

Current Therapies for Neonatal Hypoxic–Ischaemic and Infection-Sensitised Hypoxic–Ischaemic Brain Damage

“…Also, curcumin inhibits the expression of pro-inflammatory cytokines (IL-1, IL-6, and TNF-α), thus mediating inflammation and inhibiting STAT3 phosphorylation ( Maheshwari et al, 2006 ; Alexandrow et al, 2012 ). Recently, our group demonstrated that curcumin provides dose-dependent neuroprotection through immediate and delayed application following neonatal HI ( Rocha-Ferreira et al, 2019 ). Two hundred micrograms per gram BW of curcumin reduced tissue loss, microglial and astroglial activation, and cell death after HI injury in a P7 mouse model.…”

“…Prohibitin (PHB) is a protein considered essential in regulating mitochondrial structure and acting as a chaperone for the respiratory chain proteins. Curcumin administration post-HI increased PHB protein levels and provided neuroprotection through prevention of mitochondrial dysfunction during secondary energy failure ( Rocha-Ferreira et al, 2019 ). Additionally, in a study conducted by Cui et al (2017) , curcumin was administrated to P7 rats at a dose of 150 mg/kg per day for 3 days, 24 h after induced HI-injury and resulted in prevention of myelin loss ( Cui et al, 2017 ).…”