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Central nervous system (CNS) injuries, such as ischemic stroke (IS), intracerebral hemorrhage (ICH) and traumatic brain injury (TBI), are a significant global burden. The complex pathophysiology of CNS injury is comprised of primary and secondary injury. Inflammatory secondary injury is incited by damage-associated molecular patterns (DAMPs) which signal a variety of resident CNS cells and infiltrating immune cells. Extracellular cold-inducible RNA-binding protein (eCIRP) is a DAMP which acts through multiple immune and non-immune cells to promote inflammation. Despite the well-established role of eCIRP in systemic and sterile inflammation, its role in CNS injury is less elucidated. Recent literature suggests that eCIRP is a pleiotropic inflammatory mediator in CNS injury. eCIRP is also being evaluated as a clinical biomarker to indicate prognosis in CNS injuries. This review provides a broad overview of CNS injury, with a focus on immune-mediated secondary injury and neuroinflammation. We then review what is known about eCIRP in CNS injury, and its known mechanisms in both CNS and non-CNS cells, identifying opportunities for further study. We also explore eCIRP's potential as a prognostic marker of CNS injury severity and outcome. Next, we provide an overview of eCIRP-targeting therapeutics and suggest strategies to develop these agents to ameliorate CNS injury. Finally, we emphasize exploring novel molecular mechanisms, aside from neuroinflammation, by which eCIRP acts as a critical mediator with significant potential as a therapeutic target and prognostic biomarker in CNS injury. [ABSTRACT FROM AUTHOR]

Abnormal calcium homeostasis, activation of protease calpain, generation of p25 and hyperactivation of cyclin-dependent kinase 5 (Cdk5) have all been implicated in the pathogenesis of neurogenerative diseases including Alzheimer's disease. We have recently shown that extracellular cold-inducible RNA-binding protein (eCIRP) induces Cdk5 activation via p25. However, the precise molecular mechanism by which eCIRP regulates calcium signaling and calpain remains to be addressed. We hypothesized that eCIRP regulates p25 via Ca2+-dependent calpain activation. eCIRP increased calpain activity and decreased the endogenous calpain inhibitor calpastatin in Neuro 2a (N2a) cells. Calpain inhibition with calpeptin attenuated eCIRP-induced calpain activity and p25. eCIRP specifically upregulated cytosolic calpain 1, and calpain 1 silencing attenuated the eCIRP-induced increase in p25. eCIRP stimulation increased cytosolic free Ca2+, especially in hippocampal neuronal HT22 cells, which was attenuated by the eCIRP inhibitor Compound 23 (C23). Endoplasmic reticulum (ER) inositol 1,4,5-trisphosphate receptor (IP3R) inhibition using 2-aminoethoxy-diphenyl-borate or xestospongin-C (X-C), interleukin-6 receptor alpha (IL-6Rα)-neutralization, and phospholipase C (PLC) inhibition with U73122 attenuated eCIRP-induced Ca2+ increase, while Ca2+ influx across the plasma membrane remained unaffected by eCIRP. Finally, C23, IL-6Rα antibody, U73122 and X-C attenuated eCIRP-induced p25 in HT-22 cells. In conclusion, the current study uncovers eCIRP-triggered Ca2+ release from ER stores in an IL-6Rα/PLC/IP3-dependent manner as a novel molecular mechanism underlying eCIRP's induction of Cdk5 activity and potential involvement in neurodegeneration. [ABSTRACT FROM AUTHOR]

Introduction Over the last 2 decades it has become increasingly evident that hyperhomocysteinemia is an independent risk factor for thromboembolic events including stroke, coronary heart disease, venous thrombosis, and peripheral [...], Recent studies have focussed on the association between elevated homocysteine levels with megaloblastic changes and thromboembolic events, but the relationship between occult megaloblastosis (with normal haemoglobin levels) and ischaemic stroke has not been widely explored. The objective of this study is to establish a simple and economical marker for the detection of occult megaloblastosis at the community health care level in developing countries. A hundred patients who met the inclusion criteria were studied. At the 5% level of significance, the levels of cobalamin and folate were significantly lower, while the number of hypersegmented neutrophils on the peripheral smear was higher in patients from Group A (70 patients with high homocysteine) compared with the patients in Group B (30 patients with normal homocysteine). Forty-five (64.2%) of the 70 patients in Group A showed hypersegmentation of neutrophils in the peripheral smear. The high cost and difficulty in performing the vitamin assays limit their use as early markers of megaloblastosis. Hence, we conclude that in developing countries, the detection of hypersegmented neutrophils can be used at the primary healthcare level for early diagnosis of occult megaloblastosis, so that early therapeutic interventions with vitamins can prevent attacks of hyperhomocysteinemia-induced ischaemic stroke. Key words: homocysteine, hypersegmented neutrophils, cobalamin, folate. Des etudes recentes se sont concentrees sur l'association qui existe entre le niveau eleve d'homocysteine, et les changements megaloblastiques et les evenements thromboemboliques, mais la relation qui existe entre la megaloblastose occulte (avec des niveaux normaux d'hemoglobine) et l'accident ischemique cerebral n'a pas ete largement exploree. L'objectif de la presente etude consiste a developper un marqueur de detection de la megaloblastose occulte qui soit economique et facile a utiliser, dans un contexte de sante communautaire dans les pays en voie de developpement. Cent patients qui satisfaisaient aux criteres d'inclusion de l'etude ont ete recrutes. Au seuil de 5 % de signification, les niveaux de cobalamine et de folate etaient significativement plus faibles chez le groupe A (70 patients dont les niveaux d'homocysteine etaient eleves) comparativement au groupe B (30 patients dont les niveaux d'homocysteine etaient normaux), alors que le nombre de neutrophiles hypersegmentes des frottis peripheriques etait plus eleve. Quarante-cinq (64.2 %) des 70 patients du groupe A presentaient une hypersegmentation des neutrophiles dans les frottis peripheriques. Le cout eleve et la difficulte de realiser les dosages des vitamines limitent leur utilisation comme marqueurs precoces de la megaloblastose. En consequence, les auteurs concluent que dans les pays en developpement, la detection de neutrophiles hypersegmentes pourrait etre adoptee au niveau des soins de sante primaires pour diagnostiquer de maniere precoce la megaloblastose occulte, afin que des interventions therapeutiques precoces avec les vitamines puissent prevenir les accidents ischemiques cerebraux provoques par l'hyperhomocysteinemie. [Traduit par la Redaction] Mots-cles: homocysteine, neutrophiles hypersegmentes, cobalamine, folate.