Therapeutic hypothermia, or cooling of the body or brain for the purposes of preserving organ viability, is one of the most robust neuroprotectants at both the preclinical and clinical levels. Although therapeutic hypothermia has been shown to improve outcome from related clinical conditions, the significance in ischemic stroke is still under investigation. Numerous pre-clinical studies of therapeutic hypothermia has suggested optimal cooling conditions, such as depth, duration, and temporal therapeutic window for effective neuroprotection. Several studies have also explored mechanisms underlying the mechanisms of neuroprotection by therapeutic hypothermia. As such, it appears that cooling affects multiple aspects of brain pathophysiology, and regulates almost every pathway involved in the evolution of ischemic stroke. This multifaceted mechanism is thought to contribute to its strong neuroprotective effect. In order to carry out this therapy in optimal clinical settings, methodological and pathophysiological understanding is crucial. However, more investigation is still needed to better understand the underlying mechanisms of this intervention, and to overcome clinical barriers which seem to preclude the routine use therapeutic hypothermia in stroke. This article is part of the Special Issue entitled 'Cerebral Ischemia'.

AQP4, aquaporin-4BBB, blood-brain barrierIba1, ionized calcium-binding adapter molecule 1ICA, internal carotid arteryICAM-1, intracellular adhesion molecule-1I/R, ischemia/reperfusionMCAO, middle cerebral artery occlusionMMP-9, matrix metalloproteinase-9.

Triggering receptor expressed on myeloid cells-2 (TREM2) is an innate immune receptor that promotes phagocytosis by myeloid cells such as microglia and macrophages. We previously showed that TREM2 deficiency worsened outcomes from experimental stroke and impeded phagocytosis. However, myeloid cells participating in stroke pathology include both brain resident microglia and circulating macrophages. We now clarify whether TREM2 on brain microglia or circulating macrophages contribute to its beneficial role in ischemic stroke by generating bone marrow (BM) chimeric mice. BM chimera mice from TREM2 knockout (KO) or wild type (Wt) mice were used as donor and recipient mice. Mice were subjected to experimental stroke, and neurological function and infarct volume were assessed. Mice with intact TREM2 in brain microglia showed better neurological recovery and reduced infarct volumes, compared with mice lacking microglial TREM2. Myeloid cell activation and numbers of phagocytes were decreased in mice lacking brain TREM2, compared with mice with intact brain TREM2. These results suggest that TREM2 expression is important for post-stroke recovery, and that TREM2 expression on brain resident microglia is more essential to this recovery, than that of circulating macrophages. These findings might suggest a new therapeutic target for cerebrovascular diseases.

Ivy sign on FLAIR imaging is still not rare in patients with moyamoya disease, even when asymptomatic. Although optimal management is still under debate, ivy sign may be an indicator of misery perfusion, and patients with asymptomatic moyamoya disease and ivy sign on FLAIR imaging will benefit from more careful follow-up.

An 86-year-old female presented with rare bilateral chronic subdural hematomas (CSHs) of the posterior fossae which were successfully treated by surgical intervention. She had experienced mild head trauma one month before admission. She was transferred to our hospital because of consciousness disturbance and tetraparesis. Magnetic resonance (MR) imaging showed simultaneous occurrence of supratentorial and infratentorial CSHs. We tried to evacuate the CSHs of the bilateral posterior fossae because brainstem compression was markedly severe. Through bilateral burr-hole trepanations, chocolate-colored fluid, not containing clotted components, gushed out under great pressure. Postoperative course was uneventful. MR imaging revealed that the CSHs of the posterior fossae had completely disappeared and brainstem compression had also improved. The patient's neurological deficits were immediately improved after the operation. The patient was discharged one month after the operation for further rehabilitation. Trepanation and evacuation of the hematoma through the posterior fossa might be one of the therapeutic options for posterior fossa CSH, which is similar to supratentorial CSH. However, we considered that the emergency of this rare entity and the method of anesthesia were quite different from supratentorial CSH.

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Therapeutic hypothermia has consistently been shown to be a robust neuroprotectant in many labs studying different models of neurological disease Although this therapy has shown great promise, there are still challenges at the clinical level that limit the ability to apply this routinely to each pathological condition. In order to overcome issues involved in hypothermia therapy, understanding of this attractive therapy is needed. We review methodological concerns surrounding therapeutic hypothermia, introduce the current status of therapeutic cooling in various acute brain insults, and review the literature surrounding the many underlying molecular mechanisms of hypothermic neuroprotection. Because recent work has shown that body temperature can be safely lowered using pharmacological approaches, this method may be an especially attractive option for many clinical applications. Since hypothermia can affect multiple aspects of brain pathophysiology, therapeutic hypothermia also could be viewed as a model of neuroprotection, which could be used to identify potential therapeutic targets. We discuss how research in this area carries the potential to improve outcome from a variety of neurological conditions such as hypoxia, ischemia, trauma and hemorrhage.

(248 words)The robust neuroprotective effects of transarterial regional hypothermia have been demonstrated in the typical transient middle cerebral artery occlusion (tMCAO) model, but have not yet been tested in other ischemic stroke models, even though clinical ischemic conditions are diverse. In order to clarify these effects in a different ischemic stroke model, we employed a rat model of permanent MCAO (pMCAO) with transient collateral hypoperfusion (tCHP), which was achieved by direct MCA ligation through craniotomy and 1-hour bilateral common carotid artery occlusion at the beginning of pMCAO. The infusion of 20 ml/kg of 4°C cold saline (CS) or 37°C warm saline (WS) into the ipsilateral internal carotid artery (ICA) was performed for 15 minutes in intraor post-tCHP. Neurological scores, infarct/edema volumes, and neuronal apoptosis and reactive gliosis were compared between the CS and WS groups and a non-infusion control group after 48 hours of reperfusion. Although brain temperatures were only reduced by 2-3°C for 15 minutes, the CS group had significantly better neurological scores, smaller infarct/edema volumes, and less penumbral neuronal apoptosis and reactive gliosis than the control and WS groups. The post-tCHP CS group exhibited prominent neuroprotective effects, even though infarct volumes and neuronal apoptosis were reduced less than those in the intra-tCHP CS group. In conclusion, we demonstrated the neuroprotective effects of transarterial regional hypothermia in an ischemic model of pMCAO with tCHP. Even though MCAO is persistent, cold infusion via the ICA is neuroprotective for the penumbra, suggesting the wider therapeutic application of this therapy.