The objective of this Phase II application is to develop a sensitive quantitative biomarker of drug-induced neuronal degeneration, particularly associated with drugs of abuse. We have shown that during neuronal degeneration the neuronally localized protein MAP-tau is proteolytically cleaved (C-tau) in patients with head trauma and stroke. We have developed antibodies that specifically recognize C-tau. Employing C-tau ELISA and immunohistochemistry (IHC) Phase 1 studies demonstrate that after a neurotoxic dose of methamphetamine brain C-tau levels increase in a time dependent manner in the rat. Additional studies demonstrate for the first time, that MDMA ('ecstasy') is a neurotoxin utilizing our C-tau ELISA. Our quantitative C-tau studies indicate that MDMA neurotoxicity is only 3 percent of that seen after methamphetamine accounting for the inability of previous studies to demosnstrate MDMA neurotoxicity. The proposed studies will validate our C-tau neurotoxin biomarker by assessing the time course of neurotoxicity of three street drugs (MDMA, PMA and PCP dust']), an environmental neurotoxin (TMT) and a neurotoxicity 'Gold Standard'-kainic acid.
Specific Aim 1 -Product Development: Perform quality control studies and quality-controlled manufacturing of C-tau ELISA and IHC kits.
Specific Aim 2 -Product Utilization: Determine if C-tau reliably quantifies neurotoxicity caused by drugs of abuse and environmental neurotoxins. Neurotoxic doses of drugs of abuse (MDMA, PMA, PCP), an environmental neurotoxin (TMT) and kainic acid ('Gold Standard') will be administered and the time course of neurotoxicity quantified by ELISA and anatomically localized by C-tau IHC.
Our objective is to develop a sensitive biomarker for quantifying drug-induced neuronal degeneration. The National Institute on Drug Abuse has indicated that """"""""improved methods are needed for identifying, assessing and quantifying the nature and extent of neurotoxicity"""""""" of abused drugs. Currently, the primary method of identifying drug-induced neurotoxicity in animals is the selective silver stain method. This method is histochemical and non-quantitative. Our product will be both quantitative (ELISA) and more sensitive than available silver stain techniques for detecting drug-induced neurotoxicity employing immunohistochemistry. There are several markets for our product (C-tau ELISA and C-tau immunohistochemistry). Animal studies of neurotoxins, neurodegenerative diseases, head injury or stroke would be users of our C-tau technology. In the year 2000 Medline indicates there were 4,254 studies published in these areas for an estimated annual market size of $4.2 million dollars.
