ROLPASCI

Role of lysophosphatidic acid in the pathophysiology of spinal cord injury

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 Obiettivo del progetto (Objective)

'Traumatic spinal cord injury (SCI) causes permanent functional deficits due to damage to neurons and supporting cells. The primary mechanical injury triggers inflammatory changes that develops within hours and continues for several days after the injury, which then results in further exacerbation of tissue loss and functional impairments. Reducing the inflammatory response after SCI can therefore be expected to reduce secondary tissue damage and limit functional deficits. A number of mechanisms underlie the recruitment of leukocytes from the peripheral circulation, and the activation of these cells and endogenous microglia and astrocytes within the injured spinal cord. However, the molecules that trigger these responses are not completely known. Lysophosphatidic acid (LPA) is a potent, biologically active lipid mediator that has many physiological functions such as cellular Ca2 homeostasis and regulation of cytoskeleton, proliferation and survival, adhesion and migration. Recent observations suggest that LPA might be also involved in inflammation. We have preliminary data suggesting that LPA causes a rapid and potent activation of the inflammatory response in the spinal cord, which leads to demyelination and functional impairment. LPA may mediate its effects by signaling via 4 G-protein coupled receptors (LPA1-4). Selectively blocking the receptors involved in detrimental pro-inflammatory responses without affecting those that either are not involved in the pathophysiology of the SCI or might be exerting tissue protection may lead to new interventions to promote repair after SCI, for which there is currently no effective therapy.'

Introduzione (Teaser)

Spinal cord injuries (SCIs) resulting from disease or trauma can impair physiological function causing irreversible functional loss. EU-funded researchers investigated the role of lysophosphatidic acid (LPA) receptors in SCI.

Descrizione progetto (Article)

The secondary tissue damage that follows primary SCI contributes significantly to development of permanent functional disabilities. To minimise such tissue damage it is necessary to reduce the inflammatory response after a primary SCI.

LPAs are powerful biologically active lipid-mediating molecules involved in signalling via G-protein coupled receptors. They are involved in cell proliferation and other key physiological functions.

Recent research revealed that preventing LPAs from interacting with their receptors facilitated functional recovery from a spinal hemisection in mice through reduced inflammatory response. Under the aegis of the 'Role of lysophosphatidic acid in the pathophysiology of spinal cord injury' (ROLPASCI) project, researchers investigated the contribution of LPA receptors, encoded by the endothelial differentiation gene family, to SCI.

Scientists found that LPAs trigger a rapid inflammatory response in the spinal cord after injury, leading to demyelination and functional loss. Demyelination implies damage to the protective myelin sheath around nerves, resulting in neurodegeneration. In mice lacking the LPA receptors LPA1 and LPA2, researchers observed significantly reduced demyelination upon injection of LPA into the spinal cord.

Experiments revealed that LPA1 and LPA2 activation involves microglia activation, myelin and neuronal loss, and cell death. Inhibiting LPA1 or LPA2 activity significantly improved locomotion and myelin preservation after SCI, leading to better functional outcomes through neuroprotection. However, inhibiting or activating LPA3 did not negatively impact functional recovery after an SCI.

Project outcomes highlight the crucial role of LPA receptors in normal and abnormal function of the central nervous system. Targeting LPA receptors could prove to be effective in treating neurodegenerative disorders as well as SCIs.