Ischemic brain injury in adults and neonates is a significant clinical problem with limited therapeutic interventions. Currently, clinicians have only tPA available for stroke treatment and hypothermia for cerebral palsy. Owing to the lack of treatment options, there is a need for novel treatments such as stem cell therapy. Various stem cells including cells from embryo, fetus, perinatal, and adult tissues have proved effective in preclinical and small clinical trials. However, a limiting factor in the success of these treatments is the delivery of the cells and their by-products (neurotrophic factors) into the injured brain. We have demonstrated that mannitol, a drug with the potential to transiently open the blood–brain barrier and facilitate the entry of stem cells and trophic factors, as a solution to the delivery problem. The combination of stem cell therapy and mannitol may improve therapeutic outcomes in adult stroke and neonatal cerebral palsy.

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone derived from the pineal gland that has a wide range of clinical applications. While melatonin was originally assessed as a hormone specializing in regulation of the normal circadian rhythm in mammals, it now has been shown to be an effective free radical scavenger and antioxidant. Current research has focused on central nervous system (CNS) disorders, stroke in particular, for potential melatonin-based therapeutics. As of now, the realm of potential therapy regimens is focused on three main treatments: exogenously delivered melatonin, pineal gland grafting, and melatonin-mediated stem cell therapy. All therapies contain both costs and benefits, and current research is still focused on finding the best treatment plan. While comprehensive research has been conducted, more research regarding the safety of such therapies is needed in order to transition into the clinical level of testing. Antioxidants such as traditional Chinese medicine, (-)-epigallocatechin-3-gallate (EGCG), and lavender oil, which have been used for thousands of years as treatment, are now gaining recognition as effective melatonin treatment alternatives. This review will further discuss relevant studies assessing melatonin-based therapeutics and provide evidence of other natural melatonin treatment alternatives for the treatment of stroke.

Background Many clinical trials have failed despite positive laboratory findings. Stroke clinical trials are no exception, with tissue plasminogen activator (tPA) still the only effective drug for stroke with limited therapeutic window. In order to enhance the successful outcome of novel therapies in the clinic, initiatives for translational research guidelines have been pursued. In particular, the advancement of stem cell therapy for stroke from the laboratory to the clinic has now been guided by a set of recommendations called Stem cell Therapeutics as an Emerging Paradigm for Stroke or STEPS. We review here the major criteria for preclinical studies of stem cells arising from the three STEPS meetings in an effort to further emphasize the need for careful and rigorous assessment of the safety, efficacy, and mechanism of action associated with stem cell therapy for stroke. Learning from our previous mistakes and identifying gaps in knowledge will likely prevent stem cell therapy from becoming yet another statistic of failed clinical trial in stroke.

The timing of therapeutic intervention in traumatic brain injury (TBI) is critical. Although immediate cell death cascades have become established in adult TBI, the pathophysiology underlying neonatal TBI is poorly understood. The objective of the present study was to determine the role of cytokine regulation following TBI in neonatal rats. Seven-day-old Sprague-Dawley rats were subjected to TBI using the controlled cortical impact (CCI) injury model. Age-matched littermates that did not receive TBI served as the controls. Immediately following TBI, rats were euthanized, and the brains were divided into the ipsilateral and contralateral hemispheres then flash frozen. A BioRad 23-Plex panel was used to measure cytokine levels. Surprisingly, the data revealed that 18 of the 23 cytokines analyzed were significantly downregulated in the hemisphere contralateral to the TBI impacted hemisphere. IL-5, IL-6 and MIP-3a were significantly suppressed in both ipsilateral and contralateral hemispheres of neonatal TBI rats compared to the control rats. A parallel study processing the plasma of the same cohort of neonatal rats revealed no difference in the same cytokines analyzed in the brain tissue, suggesting highly localized cytokine suppression in the brain during early injury. In stark contrast to the reported early pro-inflammatory response exhibited in adult TBI, the present neonatal TBI study demonstrated a reversed cytokine profile of downregulation. These results suggest a robust, immediate anti-inflammatory response mounted by the contralateral hemisphere of the young brain.