The Role of Microglial Phagocytosis in Ischemic Stroke

Microglia are the resident immune cells of the central nervous system that exert diverse roles in the pathogenesis of ischemic stroke. During the past decades, microglial polarization and chemotactic properties have been well-studied, whereas less attention has been paid to phagocytic phenotypes of microglia in stroke. Generally, whether phagocytosis mediated by microglia plays a beneficial or detrimental role in stroke remains controversial, which calls for further investigations. Most researchers are in favor of the former proposal currently since efficient clearance of tissue debris promotes tissue reconstruction and neuronal network reorganization in part. Other scholars propose that excessively activated microglia engulf live or stressed neuronal cells, which results in neurological deficits and brain atrophy. Upon ischemia challenge, the microglia infiltrate injured brain tissue and engulf live/dead neurons, myelin debris, apoptotic cell debris, endothelial cells, and leukocytes. Cell phagocytosis is provoked by the exposure of “eat-me” signals or the loss of “don’t eat-me” signals. We supposed that microglial phagocytosis could be initiated by the specific “eat-me” signal and its corresponding receptor on the specific cell type under pathological circumstances. In this review, we will summarize phagocytic characterizations of microglia after stroke and the potential receptors responsible for this programmed biological progress. Understanding these questions precisely may help to develop appropriate phagocytic regulatory molecules, which are promoting self-limiting inflammation without damaging functional cells.

The Roles of Neurotrophins in Traumatic Brain Injury

Neurotrophins are a collection of structurally and functionally related proteins. They play important roles in many aspects of neural development, survival, and plasticity. Traumatic brain injury (TBI) leads to different levels of central nervous tissue destruction and cellular repair through various compensatory mechanisms promoted by the injured brain. Many studies have shown that neurotrophins are key modulators of neuroinflammation, apoptosis, blood–brain barrier permeability, memory capacity, and neurite regeneration. The expression of neurotrophins following TBI is affected by the severity of injury, genetic polymorphism, and different post-traumatic time points. Emerging research is focused on the potential therapeutic applications of neurotrophins in managing TBI. We conducted a comprehensive review by organizing the studies that demonstrate the role of neurotrophins in the management of TBI.

Imaging of Vascular Aphasia

Brain imaging is essential for the diagnosis of acute stroke and vascular aphasia. Magnetic resonance imaging (MRI) is the modality of choice for the etiological diagnosis of aphasia, the assessment of its severity, and the prediction of recovery. Diffusion weighted imaging is used to detect, localize, and quantify the extension of the irreversibly injured brain tissue called ischemic core. Perfusion weighted imaging (from MRI or CT) is useful to assess the extension of hypoperfused but salvageable tissue called penumbra. Functional imaging (positron emission tomography (PET), functional MRI (fMRI)) may help predicting recovery and is useful for the understanding of language networks and individual variability. This chapter is meant to review the state of the art of morphological and functional imaging of vascular aphasia and to illustrate the MRI profiles of different aphasic syndromes.

Credibility of the Neutrophil-to-Lymphocyte Count Ratio in Severe Traumatic Brain Injury

Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality worldwide. The consequences of a TBI generate the activation and accumulation of inflammatory cells. The peak number of neutrophils entering into an injured brain is observed after 24 h; however, cells infiltrate within 5 min of closed brain injury. Neutrophils release toxic molecules including free radicals, proinflammatory cytokines, and proteases that advance secondary damage. Regulatory T cells impair T cell infiltration into the central nervous system and elevate reactive astrogliosis and interferon-γ gene expression, probably inducing the process of healing. Therefore, the neutrophil-to-lymphocyte ratio (NLR) may be a low-cost, objective, and available predictor of inflammation as well as a marker of secondary injury associated with neutrophil activation. Recent studies have documented that an NLR value on admission might be effective for predicting outcome and mortality in severe brain injury patients.

WNT pathway alteration is related to dysplastic cortical tissue and not to adjacent tissue of patients with FCD and refractory epilepsy

Background Focal cortical dysplasia (FCD) is a malformation of the cortical development that cause medical refractory seizures and the only treatment may be surgical resection of the affected area of the brain. People affected by FCD may present seizures of variable severity since childhood. The physiopathology of the disease is not yet understood, however it is known that several genes alterations may play their role. The WNT/β-catenin pathway is associated with cell transformation and migration and for this reason may be crucial for understanding FCD’s aetiology. The aim of this study was to explore genes related to the WNT/β-catenin pathway in patients with FCD type II. Methods Dysplastic tissue and tissue adjacent to the primary dysplastic lesion of patients with FCD type II were obtained from two patients who underwent surgical treatment. The analysis of the relative expression of genes was performed by a qRT-PCR array containing 84 genes related to the WNT pathway. Results In patient 1, the analysis showed a difference in the expression of seven genes, demonstrating an increase in AXIN2, FRAT2, FZD9, KREMENI and PP2R1A genes and a reduction in CSNK1G3 and PPP2CA genes in dysplastic tissue. In patient 2, the analysis showed increased expression of CSNK1A1, FZD4 and PPP2CA genes, as well as reduced of CTNNBIP1 gene in dysplastic tissue. Conclusion Dysregulation in the expression of genes that control the receptors of the WNT pathway keeps it in an inactivated state. Therefore, a eventual manipulation of this pathway focusing on its activation may influence molecular manifestations underlying the epileptogenic status in injured brain tissue, which could act as a therapeutic alternative to FCD type II. The WNT/ β-catenin signaling pathway is crucial for the control of embryonic development, which takes place through the regulation of cell differentiation, migration and proliferation, and apoptosis process.

Coming to the Rescue: Regulatory T Cells for Promoting Recovery After Ischemic Stroke

Immune cell infiltration to the injured brain is a key component of the neuroinflammatory response after ischemic stroke. In contrast to the large amount of proinflammatory immune cells, regulatory T cells, are an important subgroup of T cells that are involved in maintaining immune homeostasis and suppress an overshooting immune reaction after stroke. Numerous previous reports have consistently demonstrated the beneficial role of this immunosuppressive immune cell population during the acute phase after experimental stroke by limiting inflammatory lesion progression. Two recent studies expanded now this concept and demonstrate that regulatory T cells-mediated effects also promote chronic recovery after stroke by promoting a proregenerative tissue environment. These recent findings suggest that boosting regulatory T cells could be beneficial beyond modulating the immediate neuroinflammatory response and improve chronic functional recovery.

Heparin-Induced Fever in Neurointensive Care Unit: A Rarity Yet a Possibility

Fever is considered a protective response having multitude of benefits in terms of enhancing resistance to infection, recruiting cytokines to the injured tissue, and promoting healing. In terms of an injured brain, this becomes a double-edged sword triggering an inflammatory cascade resulting in secondary brain injury. It is important to identify the etiology so that corrective measures can be taken. Here we report a case of persistent fever in a patient with Guillain-Barré syndrome, which was probably due to heparin. This is the first report of heparin-induced fever in a neurocritical care setting and third report overall.

Aspirin Exerts Neuroprotective Effects by Reversing Lipopolysaccharide-Induced Secondary Brain Injury and Inhibiting Matrix Metalloproteinase-3 Gene Expression

Objective. This study is aimed at exploring the possible neuroprotective mechanism of aspirin and the effect of bacterial endotoxin lipopolysaccharide (LPS) during cerebral ischaemia-reperfusion (CIRP) injury. Methods. We established three animal models: the CIRP, LPS, and CIRP+LPS models. Mortality, the injured brain area, and the beam walking test were used to estimate the degree of cerebral injury among the rats. Immunohistochemistry and immunofluorescence were used to detect activated microglia, matrix metalloproteinase-3 (MMP-3), and osteopontin (OPN). Results. The injured brain area and mortality were dramatically reduced ( p < 0.01 ), and the beam walking test scores were elevated ( p < 0.01 ) in the acetylsalicylic acid (ASA) group compared to the control group. The number of microglia-, MMP-3-, and OPN-positive cells also increased. Furthermore, the number of GSI-B4, OPN, and MMP-3 cells decreased in the ASA group compared to the control group. After LPS stimulation, the number of microglia reached a peak at 24 h; at 7 d, these cells disappeared. In the ASA group, the number of microglia was significantly smaller ( p < 0.05 ), especially at 24 h ( p < 0.01 ), compared to the LPS group. Moreover, the injured brain area and the mortality were dramatically increased and the beam walking test scores were reduced ( p < 0.01 ) after LPS simulation following CIRP. The degree of injury in the ASA group resembled that in the control group. However, the number of MMP-3-immunoreactive neurons or microglia was significantly larger than that of the control group ( p < 0.05 ). In the ASA group, the MMP-3 expression was also considerably decreased ( p < 0.05 ). Conclusions. After CIRP, microglia were rapidly activated and the expression of MMP-3 and OPN significantly increased. For rats injected with LPS at reperfusion, the injured brain area and mortality also dramatically increased and the neurologic impairment worsened. However, ASA exhibited a neuroprotective effect during CIRP injury. Furthermore, ASA can reverse LPS-induced cerebral injury and inhibit the inflammatory reaction after CIRP injury.

Regulation and Intervention of Intracranial Pressure

Intracranial pressure is the total amount of pressure exerted by the brain, blood and cerebrocinal fluid in the rigid cranial space. Compliance is an indicator of the brain's tolerance for increased ICP, when compliance is exceeded, there will be a dramatic increase in the pressure/volume curve so that ICP will increase rapidly. In the injured brain, cerebral blood flow (CBF) is regulated to supply sufficient oxygen and substrates to the brain. Certain physiological factors such as hypercarbia, acidosis and hypoxemia cause vasodilation which causes an increase in CBF, seizure activity and fever will increase the level of brain metabolism and CBF. Cerebral edema is the most common cause of non-traumatic brain injury such as central nervous system infections, metabolic and systemic encephalopathy. Vasogenic brain edema occurs due to injury to the blood-brain barrier and increased capillary permeability in the area around the injury, or to inflammation, especially in CNS infections. Medical management of elevated intracranial pressure includes sedation, cerebrospinal fluid drainage, and osmotherapy with either mannitol or hypertonic salts.