Analyses, using toxin fragment, of disturbances in autonomic nervous system in tetanus intoxication, a possible major cause of tetanus death

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Fragments(A-B and C) of tetanus toxin were highly purified from mildly papain-digested toxin by HPLC-gel permeation and adsorption column chromatograpies. Fragment A-B preparation(200 <mu> g), further purified by affinity chromatography using anti-fragment C antibody as ligand, had no spastic toxicity which is typical for tetanus toxin, nor blocked neuromuscular transmission in rat, but showed definite, atypical toxicity("flaccid paralysis" or "weakness") when injected intramuscularly or intravenously into mice and killed them in 2-4 days. Unlike whole toxin, purified fragment A-B, blocked both inhibitory and excitatory synapses almost at the same time after injection into cat spinal cord. Toxin injected intramuscularly or intravenously into mice did not elicit hypertension but remarkable hypotension one to half day before death. Purified fragment A-B showed similar activity in mice. Toxin(0.64-2.6 ng) injected intravenously into rat, unlike toxin injected intramuscularly, elicited abnormal hypertension and subsequent death. Intracerebroventicular injection of toxin into rat gave more reproducible effects than intravenous injection. Immunocytochemical studies by indirect fluorescent technique showed localizatin of toxin in border between area postrema and nucleus solitarius in medulla oblongata. Further exact studies are being carried out using mouse monoclonal anti-bodies against toxin fragments. Toxin injected intravenously into rabbits (first 0.3 <mu> g and then 30 <mu> g 7 days later) showed remarkable fluctuations in blood pressure having repeated hypotensive phases resembling those in severe cases of tetanus patients. Control of blood pressure in these rabbits was attempted by intravenous administration of epinephine under total spinal anaesthesia. The method was successfully applied to treatment of tetanus patients.