Biomedical subjects
Publications and source records attributed to Nancy Rothwell.
There is now considerable evidence from both experimental and clinical studies that immune and inflammatory processes can contribute to the onset of stroke and the neurologic and psychologic outcomes. Several specific therapeutic targets have been identified that may significantly improve the devastating impact of stroke.
Interleukin-1 (IL-1) expression in the brain increases in response to acute and chronic insults, and IL-1 contributes directly to experimentally induced ischaemic, excitotoxic, and traumatic brain injury. Release and cleavage of active IL-1 beta may be achieved via purinergic P2X7 receptors and activation of caspase-1. The mechanisms of action of IL-1 are largely unknown, but may involve effects on glia, endothelia, and neurones, or on physical parameters within the brain such as temperature or acidity. The naturally occurring IL-1 receptor antagonist (IL-1ra) is currently being considered for treatment of stroke and other disorders.
Neuronal injury and cell death in the central nervous system (CNS) are underlying features of neurodegenerative disorders. However, our understanding of the fundamental mechanisms involved is still limited. Inflammatory processes mediated by cytokines, and interleukin-1 (IL-1) in particular, play a significant role in neuronal death following pathological insults. Despite this growing area of research, very little is known about the factors regulating the expression, cleavage and release of interleukin-1 in the brain. Recent studies on immune cells demonstrate that extracellular ATP can act as a potent stimulus for the maturation and release of interleukin-1beta, via activation of P2X7 receptors. Stimulation of P2X7 receptors with ATP has dramatic cytotoxic properties and a wider role in neurodegenerative processes is possible. This review discusses the potential involvement of extracellular ATP and P2X7 receptors as regulators of interleukin-1-mediated neuropathologies and thus as a mediator of cell death following pathological insults.
The cytokine interleukin-1beta (IL-1beta) contributes to ischemic, excitotoxic, and traumatic brain injury. IL-1beta actions depend on interaction with a single receptor (IL-1RI), which associates with an accessory protein (IL-1RAcP), and is blocked by IL-1 receptor antagonist (IL-1ra). Here we show that in normal mice [wild-type (WT)], intracerebroventricular injection of IL-1ra markedly reduces (-50%; p < 0.01) ischemic brain damage caused by reversible occlusion of the middle cerebral artery, whereas injection of IL-1beta exacerbates damage (+45%; p < 0.05). Mice lacking IL-1RI [IL-1RI knock-out (KO)] exhibited ischemic brain damage that is almost identical to that of the WT (infarct volume 43.7 +/- 6.1 and 46.2 +/- 6.2 mm3, respectively), but failed to respond to injection of IL-1ra. However, injection of IL-1beta (intracerebroventricularly) exacerbated ischemic brain damage in IL-1RI KO (+61%; p < 0.001) and in WT mice (+45%). This effect of IL-1beta was abolished by heat denaturation in all animals, and was reversed by IL-1ra in WT, but not IL-1RI KO mice. In contrast, IL-1RI KO mice were completely resistant to effects of IL-1beta on food intake or body weight. IL-1RAcP mRNA was increased by stroke in WT, but reduced in IL-1RI KO mice compared with sham-operated mice. Type II IL-1 receptor mRNA was significantly increased 4 hr after ischemia in WT and IL-1RI KO (+20%) animals. These data show that IL-1beta can exacerbate ischemic brain damage independently of IL-1RI and suggest the existence of additional signaling receptor or receptors for IL-1 in the brain.
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Hypoxic ischemia is a common cause of brain injury in the human neonate. This can be mimicked in the neonatal rat, but produces variable injury. The present study investigated the influence of litter size on the severity and variability of damage caused by hypoxic-ischemic injury in neonatal rats. Groups of 7-d-old pups from birth-sized litters (13-15 pups), or from litters culled to 10 on postnatal d 2, and 8- and 9-d-old pups from birth-sized litters, were exposed to common carotid artery occlusion and then, 3 h later, hypoxia (2 h 15 min, 8% oxygen). Damage was assessed histologically 72 h after injury, and graded (I-IV) according to severity. In nonculled litters, similar numbers of animals had each grade of injury. Most pups (70%) from culled litters had grade III or IV damage, and severity was significantly greater than in nonculled litters (p < 0.001). Pups from culled litters were heavier (17.6 +/- 0.4 g) than pups from nonculled litters (14.7 +/- 0.3 g, p < 0.0001). To determine whether this indicated that culled litters were more similar to older pups in their response to hypoxic-ischemic injury, we examined injury in 8- and 9-d-old pups of similar body weight to 7-d-old pups from culled litters. The severity and distribution of damage in the older pups was different from damage in the 7-d-old pups from culled litters. These data suggest that in 7-d-old rats, litter size influences damage caused by hypoxic-ischemic injury, and that the relationship between body weight, brain development, and susceptibility to hypoxic-ischemic injury is complex.