An endogenous pentapeptide acting as a sodium channel blocker in inflammatory autoimmune disorders of the central nervous system

Reversible blockade of sodium channels by endogenous substances has been claimed to account for the fast exacerbations and relapses commonly seen in demyelinating autoimmune diseases(1-4). Evidence has been provided that in the cerebrospinal fluid of patients with multiple sclerosis(5) or Guillain-Barre syndrome(6), a sodium-channel-blocking factor exists that has properties of local anesthetic agents(7,8). This factor could contribute to the nerve conduction block and paresis seen in these disorders(9-11). We describe here a previously unknown endogenous substance in human cerebrospinal fluid with distinct channel-blocking properties even at very tow (0.00001 M) concentrations. The pentapeptide with the sequence Gln-Tyr-Asn-Ala-Asp exerted its blocking action by shifting the steady-state inactivation curve of the sodium channels to more-negative potentials, as most local anesthetics do. In the cerebrospinal fluid of healthy individuals, its concentration was about 3 mu M, whereas in patients with multiple sclerosis and Guillain-Barre syndrome, it increased 300-1,400%. At these concentrations, the peptide's blocking efficacy was higher than that of 50 mu M lidocaine. At a concentration of 10 mu M, lidocaine is able to 'unmask' subclinical lesions in multiple sclerosis(12); thus, the endogenous pentapeptide may well contribute to the fast changes of symptoms. Furthermore, it may become valuable as a marker of disease activity.