The role of PPAR activation during the systemic response to brain injury.

Background: Fenofibrate, a PPAR-α activator, has shown promising results as a neuroprotective therapy, with proposed anti-inflammatory and anti-oxidant effects. However, it displays poor blood-brain barrier permeability leading to some ambiguity over its mechanism of action. Experimentally induced brain injury has been shown to elicit a hepatic acute phase response that modulates leukocyte recruitment to the injured brain.

Impact of vasculature damage on the outcome of spinal cord injury: a novel collagenase-induced model may give new insights into the mechanisms involved.

The deleterious effect of vasculature damage on the outcome of spinal cord injury has long been recognized, and numerous clinical studies have shown that the presence of hemorrhage into the spinal cord is directly associated with a poorer neurological outcome. Vascular damage leads to decreased blood flow to the cord and the release of potentially toxic blood-borne components. Here we consider the mechanisms that may be contributing to hemorrhage-induced damage and discuss the utility of a new model of spinal cord hemorrhage, which was urgently required as most of our current understanding has been extrapolated from intracerebral hemorrhage studies.

The role of hemorrhage following spinal-cord injury.

Spinal-cord injury is characterized by primary damage as a direct consequence of mechanical insult, and secondary damage that is partly due to the acute inflammatory response. The extent of any hemorrhage within the injured cord is also known to be associated with the formation of intraparenchymal cavities and has been anecdotally linked to secondary damage. This study was designed to examine the contribution of blood components to the outcome of spinal-cord injury.

Investigation of immune and CNS-mediated effects of fingolimod in the focal delayed-type hypersensitivity multiple sclerosis model.

We examined the effect of fingolimod (0.1 and 0.3 mg/kg/day orally) on blood-brain barrier (BBB) function, demyelination and leukocyte recruitment at different stages of the focal delayed-type hypersensitivity (DTH) multiple sclerosis model in Lewis rats using immunohistochemistry and gadolinium (Gd)-enhancing magnetic resonance imaging (MRI).

The systemic response to brain injury and disease.

The idea that the brain is immunologically privileged and displays an atypical leukocyte recruitment profile following injury has influenced our ideas about how signals might be carried between brain and the periphery. For many, this has encouraged a cerebrocentric view of immunological responses to CNS injury, with little reference to the potential contribution from other organs. However, it is clear that bidirectional pathways between the brain and the peripheral immune system are important in the pathogenesis of CNS disease.

Liver Kupffer cells control the magnitude of the inflammatory response in the injured brain and spinal cord.

The CNS inflammatory response is regulated by hepatic chemokine synthesis, which promotes leukocytosis and facilitates leukocyte recruitment to the site of injury. To understand the role of the individual cell populations in the liver during the hepatic response to acute brain injury, we selectively depleted Kupffer cells (KC), using clodronate-filled liposomes, and assessed the inflammatory response following a microinjection of IL-1beta into the rat brain or after a compression injury in the spinal cord. We show by immunohistochemistry that KC depletion reduces neutrophil infiltration into the IL-1beta-injected brain by 70% and by 50% into the contusion-injured spinal cord.