Cationic peptides (polylysines and polyarginines) are being developed as drug delivery systems to nuclei. Therefore, a detailed description of tissue response changes upon the application of cationic peptides over intact basement membranes of excitable tissue is of interest in pharmacology. In this paper we examine the effects of two naturally occurring cationic peptides protamine (polyarginine) and crotamine (polylysine) on the optical profiles of retinal spreading depression waves (RSDs). This intrinsic optical signal (IOS), recorded non-invasively, provides information about dissipation of electrochemical gradients within the tissue and its metabolic consequences. Protamine at nanomolar range brought the tissue excitability to collapse without any signs of acute toxicity whereas crotamine, a known myotoxin from rattlesnake, decreased the tissue transparency and changed markedly the optical profiles of RSDs. Also, fluorescent crotamine was incorporated to Müller cells in a few minutes, suggesting a close membrane interaction. The optical changes brought about by crotamine were easily washed off. By contrast, the excitability collapse in presence of protamine lasted for at least two hours. Conclusions: we concluded that crotamine has fusogenic properties that alters ion transport in excitable tissue. Protamine effect seems to be similar to its effect on basement membrane of epithelium due to its property of making heteropolymers with heparan sulfate. The clinical syndrome expressed in mice after crotamine injection suggested excitotoxic CNS effects confirmed by the isolated retina experiments.