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-1beta injected into the rat striatum with the excitotoxin alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (S-AMPA) caused increased expression of IL-1beta (mRNA and protein) mainly in the cortex where maximum injury occurs. Marked increases in IL-1beta mRNA and protein were also observed in the hypothalamus. S-AMPA, injected alone into the striatum, caused only localized damage, but administration of IL-1beta 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-1beta was significantly reduced by administration of the IL-1 receptor antagonist into the lateral hypothalamus. These data suggest that IL-1beta 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.

Figure 1

Representative coronal brain sections at a single level illustrating the cell death (pale areas) observed after stereotaxic injection of S-AMPA (7.5 nmol) in the rat striatum (str), immediately followed by vehicle (A) or hrIL-1β (10 ng; B) in the LH.

Figure 2

Representative coronal brain sections at a single level illustrating the cell death (pale areas) observed after stereotaxic coinjection of hrIL-1β (10 ng) and S-AMPA (7.5 nmol) in the rat striatum (str), followed by vehicle (A) or hrIL-1ra (10 μg; B) in the LH.

Figure 3

Simplified schematic diagram illustrating putative pathways (dashed lines) involved in the effects of IL-1β on S-AMPA-mediated excitotoxic cell death in the rat brain. It is proposed that IL-1β can act via the hypothalamus (and possibly other areas) to exacerbate the effects of striatal S-AMPA and produce cell death in the cortex. SNR, substantia nigra pars reticulata; EP, endopeduncular nucleus.