Prophylactic agents acutely administered in response to insecticide intoxication or terrorist exposure to anticholinesterases can prevent toxic symptoms, including fasciculations, seizures, convulsions and death. However, anticholinesterases also have longer-term unknown pathophysiological effects making rational prophylaxis/treatment problematic. Increasing evidence suggests that excessive cholinergic stimulation, activation of glutamatergic neurons and inflammatory response induces generation of reactive oxygen and nitrogen species, leading to neuronal degeneration. Data from patients' brains and animal models have widely supported the hypothesis that neuronal oxidative damage in aging as well as neurodegeneration accompanying Alzheimer's disease, ischemic stroke and epilepsy, is a major effector contributing to neurodegeneration. Determining the precise relationships among many effectors that cause oxidative damage will greatly aid in the development of neuroprotective agents. Here we propose to use biochemical and morphologic approaches to test hypothesis that suppression of biomarkers of oxidative damage and neuroinflammation can prevent neurodegeneration induced in anticholinesterase neurotoxicity. We will achieve this objective by (1) determining the extent to which anticholinestrease exposure induce changes in novel markers of neuronal oxidative damage as well as degeneration of the dendritic system, (2) examining suppression of neuronal oxidative damage and dendritic degeneration in rat model of anticholineterase neurotoxicity by using neuroprotectants currently proposed to suppress neurodegeneration (mamantine), anti- inflammatory agent (ibuprofen) and antioxidant products with a number of proposed actions, and (3) evaluating which prostaglandine receptors are involved in enhancement or suppression of cerebral oxidative damage following anticholinesterase-induced seizures. We propose to test hypothesis that increased PGE2 is a regulator of cerebral oxidative damage by signaling through EP2 and EP3 receptors. Anticipated results will shed novel information on mechanisms of anticholinesterase-induced brain injury, pathways that protect or promote neuronal survival, and suggest novel therapeutic strategies against a class of agents that continues to pose a significant risk for millions of people worldwide. The purpose of these studies is to utilize a variety of independent experimental strategies to investigate novel therapeutic strategies against pesticide and nerve agents exposure, a class of agents that continues to pose a significant risk for millions of people worldwide. Event successfully treated seizures still results in significant mortality and morbidity; therefore, better understanding of the mechanisms of brain injury and pathways that protect or promote neuronal survival, are essential for development of efficacious treatments and preventive therapies associated with pesticide and nerve agents exposures. ? ? ?
| Milatovic, Dejan; Montine, Thomas J; Aschner, Michael (2011) Measurement of isoprostanes as markers of oxidative stress. Methods Mol Biol 758:195-204 |
| Milatovic, Dejan; Montine, Thomas J; Aschner, Michael (2011) Prostanoid signaling: dual role for prostaglandin E2 in neurotoxicity. Neurotoxicology 32:312-9 |
| Raman, Dayanidhi; Milatovic, Snjezana-Zaja; Milatovic, Dejan et al. (2011) Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1?, suppress amyloid ?-induced neurotoxicity. Toxicol Appl Pharmacol 256:300-13 |
| Williams, Jason M; Milatovic, Dejan; Gore, John C et al. (2010) Chronic exposure to manganese alters brain responses to amphetamine: a pharmacological magnetic resonance imaging study. Toxicol Sci 114:310-22 |
| Milatovic, Dejan; Montine, Thomas J; Zaja-Milatovic, Snjezana et al. (2010) Morphometric analysis in neurodegenerative disorders. Curr Protoc Toxicol Chapter 12:Unit 12.16 |
| Milatovic, Dejan; Montine, Thomas J; Zaja-Milatovic, Snjezana et al. (2010) Morphometric analysis in neurodegenerative disorders. Curr Protoc Toxicol Chapter 12:Unit12.16 |
| Zaja-Milatovic, Snjezana; Gupta, Ramesh C; Aschner, Michael et al. (2009) Protection of DFP-induced oxidative damage and neurodegeneration by antioxidants and NMDA receptor antagonist. Toxicol Appl Pharmacol 240:124-31 |
| Milatovic, Dejan; Aschner, Michael (2009) Measurement of isoprostanes as markers of oxidative stress in neuronal tissue. Curr Protoc Toxicol Chapter 12:Unit12.14 |
| Zaja-Milatovic, Snjezana; Gupta, Ramesh C; Aschner, Michael et al. (2008) Pharmacologic suppression of oxidative damage and dendritic degeneration following kainic acid-induced excitotoxicity in mouse cerebrum. Neurotoxicology 29:621-7 |
