The Anti‐Parkinson Drug Rasagiline and Its Cholinesterase Inhibitor Derivatives Exert Neuroprotection Unrelated to MAO Inhibition in Cell Culture and in Vivo

Abstract: The antiapoptotic and neuroprotective activity of irreversible monoamine oxidase (MAO) B inhibitor, rasagiline [r(+)‐N‐propargyl‐1‐aminioindan], its S‐isomer (TVP1022) and TV 3219, a novel anti‐Alzheimer cholinesterase‐MAO inhibitor drug derived from rasagiline were examined in PC12 cells cultures and in vivo. We found that these drugs have potent antiapoptotic and neuroprotective activities in response to serum and NGF withdrawal in partially neuronally differentiated PC12 cells and prevent the fall in mitochondrial membrane potential, the first step in cell death. Closed head injury studies in mice have shown that both rasagiline and TVP1022 are neuroprotective. All these compounds possess a propargyl moiety, which normally is responsible for irreversible inactivation of MAO, as is seen with rasagiline. However, neither TVP1022 nor TV3219 are MAO inhibitors, both share the antiapoptotic and neuroprotective actions of rasagiline, indicating that MAO inhibition is not a prerequisite for neuroprotection and that the propargyl moiety exhibits intrinsic neuroprotective pharmacological activity that requires identification.