Fractalkine is a recently identified chemokine that exhibits cell adhesion and chemoattractive properties. It represents a unique member of the chemokine superfamily because it is located predominantly in the brain in which it is expressed constitutively on specific subsets of neurons. To elucidate the possible role of neuronally expressed fractalkine in the inflammatory response to neuronal injury, we have analyzed the regulation of fractalkine mRNA expression and protein cleavage under conditions of neurotoxicity. We observed that mRNA encoding fractalkine is unaffected by experimental ischemic stroke (permanent middle cerebral artery occlusion) in the rat. Similarly, in vitro, levels of fractalkine mRNA were unaffected by ensuing excitotoxicity. However, when analyzed at the protein level, we found that fractalkine is rapidly cleaved from cultured neurons in response to an excitotoxic stimulus. More specifically, fractalkine cleavage preceded actual neuronal death by 2-3 hr, and, when evaluated functionally, fractalkine represented the principal chemokine released from the neurons into the culture medium upon an excitotoxic stimulus to promote chemotaxis of primary microglial and monocytic cells. We further demonstrate that cleavage of neuron-derived, chemoattractive fractalkine can be prevented by inhibition of matrix metalloproteases. These data strongly suggest that dynamic proteolytic cleavage of fractalkine from neuronal membranes in response to a neurotoxic insult, and subsequent chemoattraction of reactive immune cells, may represent an early event in the inflammatory response to neuronal injury.

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Purposeless chewing in rats was induced by the acute administration of the cholinergic agonist pilocarpine or by physostigmine. Pilocarpine-induced chewing was antagonised by the centrally acting anticholinergic drugs scopolamine, benzhexol and secoverine, but not by the peripherally acting anticholinergic drug methylscopolamine. Both benzhexol and secoverine caused dose-dependent inhibition of pilocarpine-induced chewing. The D-2 antagonist sulpiride and the D-1 antagonist SCH 23390 did not inhibit pilocarpine-induced chewing. The non-selective neuroleptics pimozide, trifluoperazine and thioridazine also were inactive. In contrast, clozapine caused a dose-related inhibition of pilocarpine-induced chewing. The alpha-1 antagonist prazosin, the alpha-2 antagonist idazoxan, the beta-antagonists propranolol and metoprolol and the H-1 antagonist mepyramine did not reduce pilocarpine-induced chewing. Purposeless chewing behaviour induced by pilocarpine was reduced in a dose-related manner by the administration of the 5-HT antagonists methiothepin and mianserin, but not by spiperone or ketanserin. These data confirm that pilocarpine-induced chewing behaviour in the rat is a model of central cholinergic activity, but suggest that a serotonergic component may be involved in the mediation of this behaviour.