RAT MODEL OF EXCITOXICITY Excitotoxicity caused by excessive glutamate contributes to brain damage and dysfunction in progressive human brain diseases. Mechanisms of excitotoxicity have been studied in vivo, but intact animal models are limited. We developed an excitotoxic animal by injecting rats daily for 21 days, with the glutamate receptor agonist, N-methyl-D-aspartate (NMDA). The brain of these rats demonstrated elevated markers of arachidonic acid (AA) metabolism and neuroinflammation (interleukin-1beta, tumor necrosis factor alpha, glial fibrillary acidic protein and inducible nitric oxide synthase), but decreased expression of the anti-apoptotic markers Bcl-2 and BDNF, and of their transcription factor, phospho-CREB. Expression of pro-apoptotic Bax, Bad, and 14-3-3zeta was increased, and neuronal loss was evident. This animal model now can be used to examine and treat processes involved in in vivo excitotoxicity relevant to human brain disease (Kim et al., 2009). SELECTIVE INVOLVEMENT OF ARACHIDONIC ACID IN NEUROINFLAMMATION In a rat model of neuroinflammation, produced by a 6-day intracerebral ventricular infusion of bacterial lipopolysaccharide, we reported marked disturbances in brain arachidonic acid (AA, 20:4n-6) metabolism. In the present study, we demonstrated that parameters of brain docosahexaenoic acid (DHA, 22:6n-3) metabolism were unaffected in this model. Selective targeting of brain AA metabolism with non-steroidal antiinflammatory or other drugs should be considered for treating human brain diseases associated with neuroinflammation (Rosenberger et al., 2010). UPREGULATED BRAIN ARACHIDONIC ACID ENZYMES IN RAT MODEL OF UNILATERAL PARKINSON DISEASE We had reported that arachidonic acid (AA) signaling is upregulated in the caudate-putamen and frontal cortex of unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, a model for asymmetrical Parkinson disease. In the present study, we confirmed that this upregulation was associated with increased expression of two enzymes involved in AA metabolism, cytosolic phospholipase A2 (cPLA2) and cyclooxygenase (COX)-2, ipsilateral to the lesion in the caudate putamen and frontal cortex. This confirms that the tonically increased ipsilateral AA signal in the lesioned rat corresponds to upregulated cPLA2 and COX-2 expression within the AA metabolic cascade;such changes, if present in Parkinson disease, may contribute to symptoms and pathology of this disorder (Lee et al., 2010). IMAGING NEUROINFLAMMATION WITH ARACHIDONIC ACID IN HIV-1 TRANSGENIC RAT Human immunodeficiency virus (HIV)-1 associated infection involves entry of virus-bearing monocytes into brain, followed by microglial activation, neuroinflammation, and upregulated arachidonic acid (AA) metabolic enzymes. The HIV-1 transgenic (Tg) rat, a noninfectious HIV-1 model, shows neurologic and behavioral abnormalities after 5 months of age. We used our in vivo imaging method with quantitative autoradiography to demonstrate that brain AA metabolism was elevated in 6-7 month old unanesthetized HIV-1 Tg rats. Brain activities of cytosolic phospholipase A2 (cPLA2-IV), secretory sPLA2, and calcium independent iPLA2-VI, which release AA and docosahexaenoic acid from membrane phospholipids, and concentrations of proinflammatory prostaglandin E2 and leukotriene B4, also were elevated, consistent with neuroinflammation and increased AA metabolism. We now plan to use our clinical method of positron emission tomography with 1-11CAA, to test whether brain AA metabolism is upregulated in HIV-1-infected patients as a marker of neuroinflammation (Basselin et al., 2010).
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