Current Neurovascular Research - Volume 1, Issue 2, 2004

Cerebral malaria (CM), one of the most common fatal complications of the heterogenous syndrome named severe malaria, is indubitably a post-infectious neurovascular pathology, as evidenced by histopathological analyses. This neurological syndrome is characterised not only by the cytoadherence of Plasmodium falciparum-infected erythrocytes, but also by morphological and functional alterations of brain microvascular endothelial cells subsequent to their interactions with circulating cells, such as platelets, monocytes, lymphocytes, and dendritic cells. During CM, host cells, in particular immune cells, are found recruited and activated at the site of sequestration, where they release various soluble molecules. Among these, cytokines play a major role in CM pathogenesis. Indeed, cerebral complications appear to be due to an imbalance between pro-inflammatory and anti-inflammatory mediators. Cytokines (notably interferon-γ, tumour necrosis factor, lymphotoxin) and chemokine receptors (notably CCR5) are also responsible for blood-brain barrier alterations and biochemical changes leading to the brain parenchymal lesions that can be observed in CM. In return, glial cells can influence blood-borne elements, and thereby worsen the pathology. Numerous problems remain to be solved, especially the sequence of pathological events, namely the order in which the circulating cells sequester on the endothelial wall. A better understanding of the molecular mechanisms involved in CM pathogenesis is needed if we are capable of preventing cerebral complications and improving the quality of patient management.

Islet-Brain (IB) proteins [also called JNK-interacting proteins (JIPs)] are scaffold proteins that are mainly expressed in the pancreatic islets and in the brain. Functionally, the IB family is composed of IB1, IB2, IB3, and IB4 each with distinct splice variants. The IB family of proteins regulates several mitogen-activated protein kinase (MAPK) pathways by tethering their components and modifying the spectrum of substrates targeted by the MAPKs. The expression of these proteins is developmentally regulated, indicating that they play important functions during brain formation. While it is currently unclear what the precise physiological functions of the IB proteins are, there are indications that they participate in subcellular targeting of signalling proteins and modulate cell survival. Synthetic derivatives of these proteins can efficiently counteract apoptotic signalling in cells and tissues and represent therefore promising protective agents against traumatic insults, including stroke and hypoxia. This review will focus on the molecular functions of the IB proteins and their potential implications in the development of several human pathologies.

Endocannabinoids are a new class of lipids, which include amides, esters and ethers of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol are the main endogenous agonists of cannabinoid receptors, able to mimic several pharmacological effects of Δ9-tetrahydrocannabinol, the active principle of Cannabis sativa preparations like hashish and marijuana. It is known that the activity of AEA is limited by cellular uptake through a specific membrane transporter, followed by intracellular degradation by a fatty acid amide hydrolase. Together with AEA and congeners these proteins form the “endocannabinoid system”. The endogenous cannabinoids were identified in brain, and also in neuronal and endothelial cells, suggesting a potential role as modulators in the central nervous system and in the periphery. This review summarises the metabolic routes for the synthesis and degradation of AEA, and the latest advances in the involvement of this lipid in neurovascular biology. In addition, the therapeutic potential of the modulation of endocannabinoid metabolism for neuronal and vascular system will be also reviewed.

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS). The acquired immune system plays a central role in the pathogenesis of MS although target antigens and effector mechanisms are still poorly defined. Studies in animal models of infectious or autoimmune encephalomyelitis suggest that the acquired immune response targeting the CNS in MS originates from the periphery. Both T and B cells undergo activation and maturation in the lymphoid system allowing them to cross the blood brain barrier and infiltrate CNS tissue. Within the CNS, they require a local proinflammatory milieu contributed by macrophages and microglia to mediate their effector function which ultimately leads to damage of myelin sheath, oligodendrocytes, and neurons. In the current review, we elucidate the role of the immune system in MS with particular emphasis on activation and migration of immune cells to the CNS, the role of CNS cells in the inflammatory process and the contribution of the immune system to damage and repair. Based on these considerations we discuss new strategies to investigate pathogenetic pathways in multiple sclerosis.

Cell death and dysfunction following traumatic brain injury (TBI) consists of a primary phase, which causes immediate consequences to cells by direct mechanical disruption of the brain, and a secondary phase which consists of delayed events initiated at the time of insult. One of the major culprits that contributes to delayed neuronal damage and death after a traumatic insult is the calcium ion. The original calcium hypothesis suggests that a large, sustained influx of calcium into cells initiates cell death signalling cascades. While much of this original tenant remains true, recent findings suggest that the role of calcium in traumatic neuronal injury may be more complex. For example, a sustained level of intracellular free calcium is not necessarily lethal, but the specific route of calcium entry may couple calcium directly to cell death pathways. Other sources of calcium, such as intracellular calcium stores, can also cause cell damage. In addition, calcium-mediated signal transduction pathways have been found to be altered following injury. These alterations are sustained for several hours and may contribute to dysfunction in neurons that do not necessarily die after a traumatic episode. This review provides an overview of experimental evidence that has led to our current understanding of the role of calcium in neuronal death and dysfunction after TBI. While the focus is on alterations in neuronal calcium homeostasis following mechanical injury, these findings may have implications for other pathological states of the brain, such as ischaemia and neurodegenerative disease.

The endoplasmic reticulum (ER) is a subcellular compartment playing a central role in folding and processing membrane and secretory proteins. The importance of these reactions for normal cellular function is indicated by the fact that blocking of these processes is potentially lethal for cells. Under conditions associated with ER dysfunction, unfolded proteins accumulate in the ER lumen. This is the warning signal of two stress responses: the unfolded protein response (UPR) required for inducing the new synthesis of chaperons to refold the unfolded proteins, and the ER-associated degradation (ERAD) to degrade unfolded proteins at the proteasome. Cells in which UPR and ERAD cannot be activated to such an extent that ER function is restored die by apoptosis. In acute pathological states of the brain, including stroke, neurotrauma and epileptic seizures, and in degenerative diseases ER function is impaired in multiple ways. These include oxidative stress, nitric oxide-induced inactivation of the ER calcium pump resulting in disturbances of ER calcium homeostasis and impairment of UPR and ERAD. Furthermore, proteasomal function is impaired which causes secondary ER dysfunction. The only way to escape this potentially lethal cycle is to induce UPR and thus to activate new synthesis of ER chaperon GRP78 to levels sufficient to refold unfolded proteins. ER dysfunction may induce a state of tolerance, impair cellular functions, or induce apoptosis, depending on the severity and duration and the cell type affected. This review focuses on the possible role of ER dysfunction in the pathological process induced by transient cerebral ischemia.

Multiple sclerosis is an inflammatory disease of the CNS and a leading cause of disability. Inflammatory mediators play an orchestrating part in lesional development leading to symptoms. Chemokines -chemoattractant cytokines - regulate the inflammatory composite of the MS lesion. This review focuses on the present data regarding CXCL10 (previously known as IP-10) and CXRC3 in multiple sclerosis, since consistent data has suggested that this chemokine/chemokine receptor pair has a pivotal role in leukocyte recruitment into the central nervous system (CNS) in multiple sclerosis.