[Abstract unavailable

Stroke is a major cause of death and long-term disability worldwide and is associated with significant clinical and socioeconomical implications, emphasizing the need for effective therapies. In fact, current therapeutic approaches, including antiplatelet and thrombolytic drugs, only partially ameliorate the clinical outcome of stroke patients because such drugs are aimed at preserving or restoring cerebral blood flow rather than at preventing the actual mechanisms associated with neuronal cell death [1,2]. 1742-4658.2008.06766.x Neuroinflammatory mediators play a crucial role in the pathophysiology of brain ischemia, exerting either deleterious effects on the progression of tissue damage or beneficial roles during recovery and repair. Within hours after the ischemic insult, increased levels of cytokines and chemokines enhance the expression of adhesion molecules on cerebral endothelial cells, facilitating the adhesion and transendothelial migration of circulating neutrophils and monocytes. These cells may accumulate in the capillaries, further impairing cerebral blood flow, or extravasate into the brain parenchyma. Infiltrating leukocytes, as well as resident brain cells, including neurons and glia, may release pro-inflammatory mediators, such as cytokines, chemokines and oxygen ⁄ nitrogen free radicals that contribute to the evolution of tissue damage. Moreover, recent studies have highlighted the involvement of matrix metalloproteinases in the propagation and regulation of neuroinflammatory responses to ischemic brain injury. These enzymes cleave protein components of the extracellular matrix such as collagen, proteoglycan and laminin, but also process a number of cell-surface and soluble proteins, including receptors and cytokines such as interleukin-1b. The present work reviewed the role of neuroinflammatory mediators in the pathophysiology of ischemic brain damage and their potential exploitation as drug targets for the treatment of cerebral ischemia.Abbreviations BBB, blood-brain barrier; COX-2, cyclooxygenase-2; ICAM-1, intercellular adhesion molecule 1; ICE, interleukin-1b-converting enzyme; IL, interleukin; IL-1ra, interleukin-1 receptor antagonist; iNOS, inducible nitric oxide synthase; MCAO, middle cerebral artery occlusion; MCP-1, monocyte chemotactic protein-1; MMP, matrix metalloproteinase; NO, nitric oxide; TNF, tumor necrosis factor. 13The development of tissue damage after an ischemic insult occurs over time, evolving within hours or several days and is dependent on both the intensity and the duration of the flow reduction, but also on flowindependent mechanisms, especially in the peri-infarct brain regions [3].A few minutes after the onset of ischemia, tissue damage occurs in the centre of ischemic injury, where cerebral blood flow is reduced by more than 80%. In this core region, cell death rapidly develops as a consequence of the acute energy failure and loss of ionic gradients associated with permanent and anoxic depolarization [4,5]. A few hours later, the infarct expands into the pen...

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Autophagy is the major intracellular degradation pathway that regulates long-lived proteins and organelles turnover. This process occurs at basal levels in all cells but it is rapidly upregulated in response to starvation and cellular stress. Although being recently implicated in neurodegeneration, it remains still unclear whether autophagy has a detrimental or protective role. In this study, we investigated the dynamics of the autophagic process in retinal tissue that has undergone transient ischemia, an experimental model that recapitulates features of ocular pathologies, including glaucoma, anterior ischemic optic neuropathy and retinal vessels occlusion. Retinal ischemia, induced in adult rats by increasing the intraocular pressure, was characterized by a reduction in the phosphatidylethanolamine-modified form of LC3 (LC3II) and by a significant decrease in Beclin-1. The latter event was associated with a proteolytic cleavage of Beclin-1, leading to the accumulation of a 50-kDa fragment. This event was prevented by intravitreal treatment with the non-competitive N-methyl-D-aspartate antagonist MK801 and calpain inhibitors or by calpain knockdown. Blockade of autophagy by pharmacological inhibition or Beclin-1 silencing in RGC-5 increased cell death, suggesting a pro-survival role of the autophagic process in this neuronal cell type. Altogether, our results provide original evidence for calpain-mediated cleavage of Beclin-1 and deregulation of basal autophagy in the rat retina that has undergone ocular ischemia/reperfusion injury.

The original observation that retinal ischemia-reperfusion reduces endogenous AEA via enhanced expression of FAAH supports the deduction that this is implicated in retinal cell loss caused by high IOP in the RGC layer.

Abstract:To infect target cells, the human immunodeficiency virus (HIV) type I (HIV-1) must engage not only the well-known CD4 molecule, but it also requires one of several recently described coreceptors. In particular, the CXCR4 (LESTR/fusin) receptor allows fusion and entry of T-tropic strains of HIV, whereas CCR5 is the major coreceptor used by primary HIV-1 strains that infect macrophages and CD4ϩ T-helper cells (M-tropic viruses). In addition, the ␣ chemokine SDF1␣ and the ␤ chemokines MIP1␣, MIP1␤, and RANTES, natural ligands of CXCR4 and CCR5, respectively, are potent soluble inhibitors of HIV infection by blocking the binding between the viral envelope glycoprotein gp120 and the coreceptors. Approximately two-thirds of individuals with acquired immunodeficiency syndrome (AIDS) show neurologic complications, which are referred to a syndrome called AIDS dementia complex or HIV-1-associated cognitive/motor complex. The HIV-1 coat glycoprotein gp120 has been proposed as the major etiologic agent for neuronal damage, mediating both direct and indirect effects on the CNS. Furthermore, recent findings showing the presence of chemokine receptors on the surface of different cell types resident in the CNS raise the possibility that the association of gp120 with these receptors may contribute to the pathogenesis of neurological dysfunction. Here, we address the possible role of ␣ and ␤ chemokines in inhibiting gp120-mediated neurotoxicity using the human neuroblastoma CHP100 cell line as an experimental model. We have previously shown that, in CHP100 cells, picomolar concentrations of gp120 produce a significant increase in cell death, which seems to proceed through a Ca 2ϩ -and NMDA receptor-dependent cascade. In this study, we gained insight into the mechanism(s) of neurotoxicity elicited by the viral glycoprotein. We found that CHP100 cells constitutively express both CXCR4 and CCR5 receptors and that stimulation with phorbol 12-myristate 13-acetate down-regulates their expression, thus preventing gp120-induced cell death. Furthermore, all the natural ligands of these receptors exerted protective effects against gp120-mediated neuronal damage, although with different efficiencies. These findings, together with our previous reports, suggest that the neuronal injury observed in HIV-1 infection could be due to direct (or indirect) interactions between the viral protein gp120 and chemokine and/or NMDA receptors. Key Words: HIV-1 gp120 -Chemokines-CXCR4 -CCR5-NMDA receptor.

In conclusion, preclinical and clinical evidence gathered so far support the notion that glaucoma is a widespread neurodegenerative condition whose common pathogenetic mechanisms with other diseases, i.e. Alzheimer Disease, should be further investigated as they may shed new light on these diseases improving both diagnosis and treatments.