Sedative Choice: The Chilling Confounder to Targeted Temperature Management.

Targeted temperature management (TTM) is a technique used in adults who lack a meaningful response after the return of spontaneous circulation following cardiac arrest (CA). The implementation of TTM is believed to improve neurological outcomes by decreasing cerebral metabolism, reducing apoptosis, and lowering oxygen demand. While this technique is recommended as a part of advanced cardiovascular life support (ACLS), there is a lack of consistency regarding drug choice and depth of sedation in TTM. In this report, the authors provide a review of the myriad of regimens outlined in research protocols and current guidelines to stimulate discussion and promote further studies pertaining to sedation strategies in TTM. Through this call to action, the ultimate goal is to develop a uniform approach to bedside practice.

Role of Toll-like receptor mediated signaling in traumatic brain injury.

The mechanisms underlying secondary brain damage following traumatic brain injury (TBI) remain unclear. A great many studies have demonstrated that inflammatory cascades contribute to brain damage through the activation of immune/inflammatory responses, including the increased release of cytokines and chemokines, and the recruitment of leukocytes. The cells and tissues damaged by primary mechanical injury release a number of endogenous factors acting as damage-associated molecular patterns (DAMPs), which initiate and perpetuate noninfectious inflammatory responses through transduction signaling pathways. Toll-like receptors (TLRs) are a transmembrane receptor family that can recognize the specific DAMPs released from damaged cells and recruit a set of adaptors leading to the activation of downstream kinases and nuclear factors which regulate the expression of inflammatory genes. The activation of inflammatory responses mediated by TLR signaling is closely associated with brain tissue damage and neurological dysfunction following TBI. TLRs and their downstream protein kinases may be potential targets for the treatment of TBI. Modulation of TLR-mediated signaling may attenuate brain damage and improve TBI outcome. In this review, we briefly discuss the role of TLR-mediated signaling in TBI and the new treatments targeting TLR signaling. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".

Genomic deletion of TLR2 induces aggravated white matter damage and deteriorated neurobehavioral functions in mouse models of Alzheimer's disease.

Toll-like receptor-2 (TLR2), a member of the TLR family, plays an important role in the initiation and regulation of immune/inflammation response, which is a critical mechanism underlying Alzheimer's disease (AD). To clarify the role of TLR2 in the pathological process of AD, in the present study, TLR2 knockout plus APPswe/PSEN1dE9 transgenic mice (AD-TLR2KO) were generated. Neurobehavioral tests and brain MRI scan were conducted on mice at the age of 12 months. Additionally, neuron loss was evaluated using NeuN staining. Amyloid ß protein (Aß), glial fibrillary acidic protein (GFAP), endogenous ligands for TLR2, and the activation of downstream signaling of TLR2 in mouse brains were detected by immunohistochemistry and Western blots. The results demonstrated that TLR2 deficit induced learning disabilities, decreased spontaneous activity, increased anxiety and depression, and led to white matter damage (WMD), brain atrophy, loss of neurons, and glial activation. Moreover, TLR2 deficit aggravated impaired neurobehavioral functions and WMD in AD mice, but did not affect the Aß deposition in mouse brains. Our data indicate that the genomic deletion of TLR2 impairs neurobehavioral functions, induces WMD and brain atrophy, and increases the activation of astrocytes, which in turn aggravate the symptoms of AD through a non-Aß mechanism.

Gender difference in the effect of progesterone on neonatal hypoxic/ischemic brain injury in mouse.

This study investigated the effects of progesterone (PROG) on neonatal hypoxic/ischemic (NHI) brain injury, the differences in effects between genders, and the underlying mechanisms. NHI brain injury was established in both male and female neonatal mice induced by occlusion of the left common carotid artery followed by hypoxia. The mice were treated with PROG or vehicle. Fluoro-Jade B staining (F-JB), long term behavior testing, and brain magnetic resonance image (MRI) were applied to evaluate neuronal death, neurological function, and brain damage. The underlying molecular mechanisms were also investigated by Western blots. The results showed that, in the male mice, administration of PROG significantly reduced neuronal death, improved the learning and memory function impaired by cerebral HI, decreased infarct size, and maintained the thickness of the cortex after cerebral HI. PROG treatment, however, did not show significant neuroprotective effects on female mice subjected to HI. In addition, the data demonstrated a gender difference in the expression of tumor necrosis factor receptor 1 (TNFR1), TNF receptor associated factor 6 (TRAF6), Fas associated protein with death domain (FADD), and TIR-domain-containing adapter-inducing interferon-ß (TRIF) between males and females. Our results indicated that treatment with PROG had beneficial effects on NHI injured brain in acute stage and improved the long term cognitive function impaired by cerebral HI in male mice. In addition, the activation of TNF and TRIF mediated signaling in response to cerebral HI and the treatment of PROG varied between genders, which highly suggested that gender differences should be emphasized in evaluating neonatal HI brain injury and PROG effects, as well as the underlying mechanisms.

5-hydroxymethylcytosine is detected in RNA from mouse brain tissues.

5-hydroxymethylcytosine (5hmC) is considered as a novel DNA modification and plays an important role in cancer, stem cells, and developmental diseases. In this study, we demonstrated the existence of RNA 5hmC modification in mouse brain RNA by using a dot blot analysis method. Our data indicated that 5hmC modification in RNA samples was less than that in DNA samples. Further, we optimized the conditions for 5hmC detection in RNA samples such as DNase treatment, denature reagents, denature time, sample air-dry time, and the cross-linking time between RNA and membrane. Our results demonstrated that DNase treatment and denature reagents were two important factors that affected the 5hmC detection in RNA samples. By using the optimal conditions for RNA 5hmC detection, we found that the brainstem, the hippocampus, and the cerebellum had high levels of 5hmC modification and 5mC modification in RNA. Finally, we found that RNA 5hmC modification decreased in MPTP-induced Parkinson's disease model in mice. These suggest that 5hmC modification in RNA might play an important regulative role on protein or microRNA expression in these brain tissues. Because DNA 5hmC modification plays an important role in neural differentiation and development as well as neurological diseases, the significance of 5hmC modification in RNA in different neurological diseases needs further investigation. In summary, our study demonstrated for the first time the abundance of 5hmC modification in brain RNA by using a dot blot analysis method and proved that dot blot analysis is a useful method for 5hmC detection in RNA samples.

TAK-242, an antagonist for Toll-like receptor 4, protects against acute cerebral ischemia/reperfusion injury in mice.

Toll-like receptor 4 (TLR4) contributes to cerebral ischemia/reperfusion (I/R) injury and is a potential target for the treatment of ischemic stroke. This experiment is to evaluate the effect of an exogenous TLR4 antagonist, TAK-242, against acute cerebral I/R injury. A mouse model of cerebral I/R was induced by transient middle cerebral artery occlusion. TAK-242 (3 mg/kg body weight) was injected intraperitoneally 1 hour after ischemia. Our results showed that the concentration of TAK-242 in plasma increased to 52.0 ng/mL 3 hours after injection, was maintained at 54.1 ng/mL 8 hours after injection, and decreased to 22.6 ng/mL 24 hours after injection. The concentration of TAK-242 in brain tissue increased to 26.1 ng/mL in ischemic hemisphere and 14.2 ng/mL in nonischemic hemisphere 3 hours after injection, and was maintained at the similar levels 24 hours after injection. We found that TAK-242 significantly reduced cerebral infarction compared with vehicle control, improved neurologic function, inhibited the phosphorylation of downstream protein kinases in TLR4 signaling pathway, and downregulated the expression of inflammatory cytokines. We conclude that TAK-242 is able to cross blood-brain barrier, blocks TLR4 signaling, mediates the expression of inflammatory cytokines, and protects the brain from acute damage induced by I/R.

Combined use of spatial restraint stress and middle cerebral artery occlusion is a novel model of post-stroke depression in mice.

Post stroke depression (PSD) is one of the most common complications of ischemic stroke. At present, the underlying mechanisms are unclear, largely because there are no reliable, valid and reproducible animal models of PSD. Here we report a novel animal model of PSD that displays consistent and reliable clinical features of hemiplegic stroke. The animal model encompasses a combination of the middle cerebral artery occlusion (MCAO) and spatial restraint stress. We found that a 60-minute MCAO followed by spatial restraint stress for 2 h daily for 2 to 4 weeks from the fourth day after MCAO induced PSD-like depressive phenotypes in mice. Importantly, the mice showed exacerbated deficits of neurological functions and decreased body weights, which were accompanied with reduced levels of brain derived neurotrophic factor and neurotransmitters including serotonin and dopamine. In addition, we identified increased levels of serum cortisol in our PSD mice. Finally, we found that mice with PSD were responsive to the tri-cyclic antidepressant imipramine as evidenced by their attenuated depressive behaviors, increased body weights, recovered brain serotonin levels, and decreased serum cortisol levels. This mouse model replicates multiple features of human post-stroke depression and thus provides a new model for the investigation of PSD.