Site-specific actions of interleukin-1 on excitotoxic cell death in the rat striatum

The pro-inflammatory cytokine interleukin-1 (IL-1) contributes to and exacerbates many forms of neurodegeneration. When co-administered with the potent glutamatergic agonist S-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (S-AMPA) in the rat striatum, IL-1 induces marked and widespread cell death throughout the ipsilateral cortex. The mechanisms underlying this action of IL-1 are not known but may involve activation of polysynaptic neuronal pathways leading from the striatum to the cortex via other brain areas such as the hypothalamus. The aims of the present study were to identify specific sites of action of IL-1 in the rat striatum, in order to further understand these pathways. Ventral regions of the caudate-putamen and the lateral shell of the nucleus accumbens (NAcc) were particularly sensitive to the effects of IL-1 on excitotoxic damage. A high percentage of co-injections in these sites induced distant cortical damage, whereas injections in more dorsal areas of the caudate-putamen or core regions of the NAcc were less likely to result in cortical cell death. The 'positive' injection sites differ from the unresponsive areas in that they have extensive connections with the limbic system and it may be that IL-1 displays specific actions on limbic pathways that, in conjunction with AMPA/kainate receptor activation, contribute to the remote cell death in the cortex. These findings enhance our understanding of the actions of IL-1, and the mechanisms by which it participates in neurodegeneration through both local and long-range effects.