Each year, about six million children, including 1.5 million infants, in the United States undergo surgery with general anesthesia, often requiring repeated exposures. However, a crucial question remains of whether neonatal anesthetics are safe for the developing central nervous system (CNS). General anesthesia encompasses the administration of agents that induce analgesic, sedative, and muscle relaxant effects. Although the mechanisms of action of general anesthetics are still not completely understood, recent data have suggested that anesthetics primarily modulate two major neurotransmitter receptor groups, either by inhibiting N-methyl-D-aspartate (NMDA) receptors, or conversely by activating γ-aminobutyric acid (GABA) receptors. Both of these mechanisms result in the same effect of inhibiting excitatory activity of neurons. In developing brains, which are more sensitive to disruptions in activity-dependent plasticity, this transient inhibition may have longterm neurodevelopmental consequences. Accumulating reports from preclinical studies show that anesthetics in neonates cause cellular toxicity including apoptosis and neurodegeneration in the developing brain. Importantly, animal and clinical studies indicate that exposure to general anesthetics may affect CNS development, resulting in long-lasting cognitive and behavioral deficiencies, such as learning and memory deficits, as well as abnormalities in social memory and social activity. While the casual relationship between cellular toxicity and neurological impairments is still not clear, recent reports in animal experiments showed that anesthetics in neonates can affect neurogenesis, which could be a possible mechanism underlying the chronic effect of anesthetics. Understanding the cellular and molecular mechanisms of anesthetic effects will help to define the scope of the problem in humans and may lead to preventive and therapeutic strategies. Therefore, in this review, we summarize the current evidence on neonatal anesthetic effects in the developmental CNS and discuss how factors influencing these processes can be translated into new therapeutic strategies.
Hemorrhagic strok e is a devastating disease that lacks effective therapies. In the present investigation, we tested 6-bromoindirubin-3¢-oxime (BIO) as a selective glycogen synthase kinase-3b (GSK-3b) inhibitor in a mouse model of intracerebral hemorrhage (ICH). ICH was induced by injection of collagenase IV into the striatum of 8- to 10-week-old C57BL/6 mice. BIO (8 µg/kg, IP) was administered following either an acute delivery (0–2 h delay) or a prolonged regimen (every 48 h starting at 3 days post-ICH). At 2 days post-ICH, the acute BIO treatment significantly reduced the hematoma volume. In the perihematoma regions, BIO administration blocked GSK-3b phosphorylation/activation, increased Bcl-2 and b-catenin levels, and significantly increased viability of neurons and other cell types. The prolonged BIO regimen maintained a higher level of b-catenin, upregulated VEGF and BDNF, and promoted neurogenesis and angiogenesis in peri-injury zones at 14 days after ICH. The BIO treatment also promoted proliferation of neural stem cells (NSCs) and migration of nascent DCX + neuroblasts from the subventricular zone (SVZ) to the lesioned cortex. BIO improved functional outcomes on both the neurological severity score and rotarod tests. The findings of this study corroborate the neuroprotective and regenerative effects of BIO and suggest that the Wnt/GSK-3b/b-catenin pathway may be explored for the treatment of acute or chronic ICH.
Stroke is a leading cause of disability and death, yet effective treatments for acute stroke has been very limited. Thus far, tissue plasminogen activator has been the only FDA-approved drug for thrombolytic treatment of ischemic stroke patients, yet its application is only applicable to less than 4-5% of stroke patients due to the narrow therapeutic window (< 4.5 hours after the onset of stroke) and the high risk of hemorrhagic transformation. Emerging evidence from basic and clinical studies has shown that therapeutic hypothermia, also known as targeted temperature management, can be a promising therapy for patients with different types of stroke. Moreover, the success in animal models using pharmacologically induced hypothermia (PIH) has gained increasing momentum for clinical translation of hypothermic therapy. This review provides an updated overview of the mechanisms and protective effects of therapeutic hypothermia, as well as the recent development and findings behind PIH treatment. It is expected that a safe and effective hypothermic therapy has a high translational potential for clinical treatment of patients with stroke and other CNS injuries.