Role of src‐family tyrosine kinases in excitotoxicity of the rat cerebellum

Various neurons in the CNS exhibit selective vulnerability to AMPA (α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepriopionic acid)‐induced delayed neurotoxicity known as dark cell degeneration (DCD). DCD is characterized by morphological changes including cytoplasmic and nuclear condensation, neuronal shrinkage, formation of cytoplasmic vacuoles and general failure of physiology. We are currently investigating the role of tyrosine kinases in the expression of excitotoxicity. Of particular interest is a member of the Src‐family of non‐receptor protein tyrosine kinases (PTKs), Lyn. Lyn has been shown to coimmunoprecipitate with the AMPA receptor, providing a mechanism of early activation of tyrosine kinases following AMPA insult. Lyn, and other tyrosine kinases, have been shown to regulate downstream effectors including the MAPK pathway. Two inhibitors, Lavendustin A and PP2 are being utilized to study the effects of tyrosine kinases in the expression of DCD. Lavendustin A, a general inhibitor of tyrosine phosphorylation was successful at inhibiting AMPA‐induced degeneration. Also of interest is the effects that these inhibitors have on the activation of the MAP kinases, JNK, P38 and ERK1/2. These MAP kinases have been shown to be activated in the cerebellum following AMPA insult and we have now begun looking at changes in activation caused by Lavendustin A and PP2. Early activation of JNK following AMPA insult is slightly inhibited by PP2 and Lavendustin A indicating that tyrosine kinases are likely involved in various mechanisms of action leading to the expression of DCD in the cerebellum.