Cortical cell death induced by IL-1 is mediated via actions in the hypothalamus of the rat

Abstract

The cytokine IL-1 mediates diverse forms of neurodegeneration, but its mechanism of action is unknown. We have demonstrated previously that exogenous and endogenous IL-1 acts specifically in the rat striatum to dramatically enhance ischemic and excitotoxic brain damage and cause extensive cortical injury. Here we tested the hypothesis that this distant effect of IL-1 is mediated through polysynaptic striatal outputs to the cortex via the hypothalamus. We show that IL-1␤ injected into the rat striatum with the excitotoxin ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (S-AMPA) caused increased expression of IL-1␤ (mRNA and protein) mainly in the cortex where maximum injury occurs. Marked increases in IL-1␤ mRNA and protein were also observed in the hypothalamus. S-AMPA, injected alone into the striatum, caused only localized damage, but administration of IL-1␤ into either the striatum or the lateral hypothalamus immediately after striatal S-AMPA resulted in widespread cell loss throughout the ipsilateral cortex. Finally we showed that the cortical cell death produced by striatal coinjection of S-AMPA and IL-1␤ was significantly reduced by administration of the IL-1 receptor antagonist into the lateral hypothalamus. These data suggest that IL-1␤ can act in the hypothalamus to modify cell viability in the cortex. We conclude that IL-1-dependent pathways project from the striatum to the cortex via the hypothalamus and lead to cortical injury, and that these may contribute to a number of human neurological conditions including stroke and head trauma. E xcessive activation of glutamate receptors (excitotoxicity) contributes to a number of neurodegenerative disorders (1). Thus direct injection of glutamatergic agonists into the brains of experimental animals has proved a useful model to study, in vivo, the underlying mechanisms of cell death in such acute conditions. There is increasing interest in the role of inflammatory mediators such as IL-1 in cell death in this and other forms of neurodegeneration, such as cerebral ischemia (2).The cytokine IL-1 has diverse actions in the brain and mediates acute experimental neurodegeneration (3). Injection or overexpression of IL-1 receptor antagonist (IL-1ra) significantly inhibits neuronal damage induced in rodents by focal cerebral ischemia, traumatic brain injury, or excitotoxin administration (see ref.2). Administration of exogenous IL-1␤ fails to cause neuronal death in normal rat brain but markedly exacerbates ischemic, traumatic, or excitotoxic brain injury (4-6). When IL-1␤ is coinjected with ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (S-AMPA) in the rat striatum, extensive cell death occurs throughout the ipsilateral cortex, which is not observed after S-AMPA alone (6). The mechanism of this potent effect of IL-1␤ is not known, although in focal cerebral ischemia, exacerbation by IL-1␤ and neuroprotective actions of IL-1ra are also mediated through actions in the striatum that influence cortical damage (7). Because excitotoxicity contributes to many forms of n...

System xc−Activity and Astrocytes Are Necessary for Interleukin-1β-Mediated Hypoxic Neuronal Injury

“…The fact that ionotropic glutamate receptor antagonism prevents the potentiation of hypoxic neuronal injury by IL-1␤ indicates that these changes are not merely correlative but represent the cause of injury. A link between glutamate receptormediated injury and IL-1␤ is further strengthened by in vivo evidence showing that intrastriatal injection of IL-1␤ enhances excitotoxic neuronal injury (Lawrence et al, 1998;Stroemer and Rothwell, 1998;Allan et al, 2000), whereas striatal and hippocampal neuronal injury induced by direct NMDA receptor 4 except supernatant was collected after 120 min of oxygen deprivation to measure accumulation of glutamate in the bathing medium via HPLC. Data are expressed as the mean Ϯ SEM glutamate accumulation in micromolar (n ϭ 4 -5 cultures pooled from 2 different experiments).…”

Neuroinflammation and Both Cytotoxic and Vasogenic Edema Are Reduced in Interleukin-1 Type 1 Receptor-Deficient Mice Conferring Neuroprotection

“…19 Increased NO release from activated leukocytes and astrocytes leads to the production of peroxynitrite, which can irreversibly damage lipids and proteins causing cell death, 18 and extensive neocortical injury occurs as a consequence of enhanced glutamate excitotoxicity after IL-1␤ injection into the striatum or hypothalamus. 20 These are not separate pathophysiological mechanisms, because NO can enhance glutamate excitotoxicity. 16 Although iNOS Ϫ/Ϫ mice have lower infarct volumes compared with WT, the neuroprotection is only partially observed in the neocortex.…”

Role of IL-1α and IL-1β in Ischemic Brain Damage

“…Both IL-1 ligands (IL-1␣ and IL-1␤) are produced rapidly in the brains of rodents exposed to cerebral ischemia (Wang et al, 1994;Hillhouse et al, 1998;Zhang et al, 1998), and recombinant IL-1␤ administered intracerebroventricularly, or directly into the brain, enhances ischemic and other forms of injury (Yamasaki et al, 1995;Loddick and Rothwell, 1996;Lawrence et al, 1998;Stroemer and Rothwell, 1998;Allan et al, 2000). Conversely, blocking IL-1 actions, by administration of the naturally occurring and selective IL-1 receptor antagonist (IL-1ra), markedly reduces neuronal loss and inflammation induced by a variety of experimental brain insults (Relton and Rothwell, 1992;Lin et al, 1995;Betz et al, 1995;Garcia et al, 1995;Yamasaki et al, 1995;Loddick and Rothwell, 1996;Stroemer and Rothwell, 1998;Yang et al, 1998).…”

“…Both cytokines are induced in response to cerebral ischemia (Touzani et al, 1999) or excitotoxicity, and central administration of IL-1␤ exacerbates damage (Allan et al, , 2000Lawrence et al, 1998). Yamasaki et al (1995) reported that intracerebroventricular injection of neutralizing anti-IL-1␤ antibody to rats reduces ischemic brain damage, implicating IL-1␤ as the major mediator of injury.…”