✓ The mechanisms that give rise to ischemic brain damage have not been definitively determined, but considerable evidence exists that three major factors are involved: increases in the intercellular cytosolic calcium concentration (Ca++i), acidosis, and production of free radicals. A nonphysiological rise in Ca++i due to a disturbed pump/leak relationship for calcium is believed to cause cell damage by overactivation of lipases and proteases and possibly also of endonucleases, and by alterations of protein phosphorylation, which secondarily affects protein synthesis and genome expression. The severity of this disturbance depends on the density of ischemia. In complete or near-complete ischemia of the cardiac arrest type, pump activity has ceased and the calcium leak is enhanced by the massive release of excitatory amino acids. As a result, multiple calcium channels are opened. This is probably the scenario in the focus of an ischemic lesion due to middle cerebral artery occlusion. Such ischemic tissues ca...

Pathophysiology and treatment of focal cerebral ischemia. Part II: Mechanisms of damage and treatment.

tance, impaired drug clearance, and mild coagulopathy. Targeted interventions are required to effectively manage these side effects. Hypothermia does not decrease myocardial contractility or induce hypotension if hypovolemia is corrected, and preliminary evidence suggests that it can be safely used in patients with cardiac shock. Cardiac output will decrease due to hypothermiainduced bradycardia, but given that metabolic rate also decreases the balance between supply and demand, is usually maintained or improved. In contrast to deep hypothermia (<30°C), moderate hypothermia does not induce arrhythmias; indeed, the evidence suggests that arrhythmias can be prevented and/or more easily treated under hypothermic conditions. Conclusions: Therapeutic hypothermia is a highly promising treatment, but the potential side effects need to be properly managed particularly if prolonged treatment periods are required. Understanding the underlying mechanisms, awareness of physiological changes associated with cooling, and prevention of potential side effects are all key factors for its effective clinical usage. (Crit Care Med 2009; 37[Suppl.]:S186 –S202)

https://emcrit.org/wp-content/hypoarts/polderman%20mechs%20of%20hypothermia.pdf

Mechanisms of action, physiological effects, and complications of hypothermia.

We monitor cellular responses to a penetrating wound in the cerebral cortex of adult rat during the first weeks after injury. Two classes of activated mononuclear phagocytes containing acetylated low-density lipoprotein (ac-LDL) receptors appear within hours at the wound site. One type of cell surrounding the lesion edge had thin, delicate processes and is identical in appearance to ramified microglia found in developing brain. Within the lesion, round cells are recognized as blood-borne macrophages when labeled by intravenous injection of carbon particles. Thus, both process-bearing reactive microglia and invading macrophages respond to brain trauma. The greatest number of ac-LDL(+) or nonspecific esterase(+) mononuclear phagocytes appears 2 days after injury within the wound site and are associated with a peak production of the cytokine interleukin-1 (IL-1). Because intracerebral infusion of IL-1 is known to stimulate astrogliosis and neovascularization (Giulian et al., 1988), we examine the time course of injury-induced reactive astrogliosis and angiogenesis. A 5-fold increase in the number of reactive astroglia is found at 3 d and a marked neovascularization at 5 d after injury. During the first week, mononuclear phagocytes engulf particles and clear them from the wound site either by migrating to the brain surface or by entering newly formed brain vasculature. To investigate further the role of reactive brain mononuclear phagocytes in CNS injury, we use drugs to inhibit trauma-induced inflammation. When applied in vivo, chloroquine or colchicine reduce the number of mononuclear phagocytes in damaged brain, help to block reactive astrogliosis and neovascularization, and slow the rate of debris clearance from sites of traumatic injury. In contrast, the glucocorticoid dexamethasone neither reduces the number of brain inflammatory cells nor hampers such responses as phagocytosis, astrogliosis, neovascularization, or debris clearance in vivo. Our observations show that mononuclear phagocytes play a major role in wound healing after CNS trauma with some events controlled by secretion of cytokines. Moreover, certain classes of immunosuppressive drugs may be useful in the treatment of acute brain injury.

https://www.jneurosci.org/content/jneuro/9/12/4416.full.pdf

The role of mononuclear phagocytes in wound healing after traumatic injury to adult mammalian brain

Purpose To characterize early structural gliotic reactions in retinal Muller cells, astrocytes, and microglia in experimentally induced diabetes. Methods Rats were rendered diabetic by streptozotocin injection and killed after 2, 4, 12, or 20 weeks. Cell densities were determined in flatmounted retinas or transverse semithin sections. Expression of glial fibrillary acidic protein (GFAP) was localized on frozen sections or flatmounts by immunofluorescence and confocal microscopy, and GFAP content was evaluated by Western blot analysis. Microglial cells were visualized by binding of isolectin B4 or staining with antibodies to phosphotyrosine residues. The integrity of the blood-retinal barrier was assessed by intravenous injection of Evans blue. Results The density of Muller cells and microglia was significantly increased at 4 weeks of diabetes compared with nondiabetic controls. GFAP expression in Muller cells was not detected at 4 weeks but was prominent at 12 weeks. The number of astrocytes was significantly reduced at 4 weeks in the peripapillary and far peripheral retina. Shape changes of microglial cells indicated functional activation. Leakage of the blood-retinal barrier was observed at 2 weeks of hyperglycemia, the earliest time point investigated. Conclusions The leakage of the blood-retinal barrier before glial reactivity suggests that glia are early targets of vascular hyperpermeability. The individual glial cell types react differentially to the diabetic state. Muller cells undergo hyperplasia preceding GFAP expression, and microglial cells are activated, whereas astrocytes regress. This glial behavior may contribute decisively to the onset and development of neuropathy in the diabetic retina.

Glial reactivity, an early feature of diabetic retinopathy.

Background—There is little consistency in the measurement of outcome in acute stroke trials, and this may complicate interpretation of the results and reduce the likelihood of detecting worthwhile drug effects. This study aims to investigate empirically the measures used to date and to give recommendations for future studies. Summary of Comment—A systematic review of all published randomized studies of acute stroke drug intervention was undertaken, and the measures used were recorded. Fifty-one studies involving 57 214 subjects were identified. These studies used 14 different measures of impairment, 11 different measures of activity, 1 measure of “quality of life,” and 8 miscellaneous other measures. Timing of outcome assessments varied from 1 week to 1 year, with the modal time being 3 months. Many studies used ordinal measures but dichotomized results for analysis. Of the 51 studies included in the review, only 21 demonstrated benefit with the defined primary outcome measure. In several studies, however...

https://www.ahajournals.org/doi/pdf/10.1161/01.STR.31.6.1429

Outcome Measures in Acute Stroke Trials A Systematic Review and Some Recommendations to Improve Practice

Our understanding of the biochemistry and biologic actions of AA metabolites has been greatly expanded in recent years. The discoveries of TXA2, PGI2, and LTs have fostered new concepts of the pathophysiology of cerebral ischemia. New approaches to treatment of ischemia include seeking an optimal dose of aspirin, developing drugs that selectively inhibit or antagonize TXA2 or LTs, and administering PGI2 or its analogues. Altering the dietary content of essential fatty acids for prophylaxis is also being studied. Though the results of this thrust are still preliminary, the exploration of these therapeutic strategies in cerebrovascular disorders based on further understanding of the pathophysiologic roles of TXA2, PGI2, LTs and probably other AA metabolites is anticipated with some optimism.

Thromboxane, prostacyclin, and leukotrienes in cerebral ischemia.

The therapeutic efficacy of prostacyclin in nonhemorrhagic cerebral infarction was assessed in a placebo-controlled double-blind trial. A total of 80 patients with stroke onset within 24 hours were randomized into placebo (37 patients) and prostacyclin (43 patients) groups. Demographic data and risk factors were comparable. Patients in the prostacyclin group received a continuous i.v. infusion of prostacyclin at an average rate of 8.5 ng/kg/min for an average of 64 hours. The placebo group received vehicle only in a similar fashion. During treatment hemodynamic changes were more prominent in the patients receiving prostacyclin and included reduction of systolic and diastolic blood pressure and increase in pulse rate. In contrast there was only a slight (but significant) reduction of diastolic blood pressure in the placebo group. Neurologic deficit scores were determined on admission, at Day 3, and at Weeks 1, 2, and 4. Mean neurologic deficit scores upon entry were comparable in the placebo and prostacyclin groups, and a significant improvement in the score for neurologic deficit was noted in both. The placebo group tended to fare better throughout the study, with a significant difference in neurologic deficit score favoring the placebo group at Week 2 (p = 0.0048). Two patients in the placebo and one in the prostacyclin group died. The only difference in adverse reactions was flushing (6 patients in prostacyclin vs. 0 in placebo group, p less than 0.05). The results of this study suggest a lack of therapeutic efficacy of prostacyclin in a defined population of patients with nonhemorrhagic cerebral infarction.

https://www.ahajournals.org/doi/pdf/10.1161/01.STR.18.2.352

O. I. Linet

Papers

Thromboxane, prostacyclin, and leukotrienes in cerebral ischemia.

Intravenous prostacyclin in acute nonhemorrhagic stroke: a placebo-controlled double-blind trial.