RTI uses cookies to offer you the best experience online. By clicking “accept” on this website, you opt in and you agree to the use of cookies. If you would like to know more about how RTI uses cookies and how to manage them please view our Privacy Policy here. You can “opt out” or change your mind by visiting: http://optout.aboutads.info/. Click “accept” to agree.
Unregulated microglial activation has been implicated as a pivotal factor contributing to Parkinson's disease. Using mesencephalic neuron-glia cultures, we address the novel possibility that peptides endogenous to the substantia nigra (SN), substance P and dynorphin (10(-13)-10(-14) M), are opposing mediators of microglial activation and consequent DA neurotoxicity. Here, we identify that substance P (10(-13)-10(-14) M) is selectively toxic to DA neurons in a microglia-dependent manner. Mechanistically, substance P (10(-13)-10(-14) M) activated microglial NADPH oxidase to produce extracellular superoxide and intracellular reactive oxygen species (ROS). Neuron-glia cultures from mice lacking a functional NADPH oxidase complex (PHOX-/-) were insensitive to substance P (10(-13)-10(-14) M) -induced loss of DA neuron function. Mixed glia cultures from (PHOX-/-) mice failed to show a significant increase in intracellular ROS in response to substance P compared with control cultures (PHOX+/+). Further, dynorphin (10(-14) M) inhibited substance P (10(-13) M) -induced loss of [3H] DA uptake. Here we demonstrate a tightly regulated mechanism governing microglia-derived oxidative stress, where the neuropeptide balance of dynorphin and substance P is critical to DA neuron survival