RESUMEN
Unrelenting cognitive and mood impairments concomitant with incessant oxidative stress and neuroinflammation are among the significant symptoms of chronic Gulf War Illness (GWI). Curcumin (CUR), an antiinflammatory compound, has shown promise to alleviate brain dysfunction in a model of GWI following intraperitoneal administrations at a high dose. However, low bioavailability after oral treatment has hampered its clinical translation. Therefore, this study investigated the efficacy of low-dose, intermittent, oral polymer nanoparticle encapsulated CUR (nCUR) for improving brain function in a rat model of chronic GWI. Intermittent administration of 10 or 20 mg/Kg nCUR for 8 weeks in the early phase of GWI improved brain function and reduced oxidative stress (OS) and neuroinflammation. We next examined the efficacy of 12-weeks of intermittent nCUR at 10 mg/Kg in GWI animals, with treatment commencing 8 months after exposure to GWI-related chemicals and stress, mimicking treatment for the persistent cognitive and mood dysfunction displayed by veterans with GWI. GWI rats receiving nCUR exhibited better cognitive and mood function associated with improved mitochondrial function and diminished neuroinflammation in the hippocampus. Improved mitochondrial function was evident from normalized expression of OS markers, antioxidants, and mitochondrial electron transport genes, and complex proteins. Lessened neuroinflammation was noticeable from reductions in astrocyte hypertrophy, NF-kB, activated microglia with NLRP3 inflammasomes, and multiple proinflammatory cytokines. Moreover, nCUR treated animals displayed enhanced neurogenesis with a normalized expression of synaptophysin puncta, and multiple genes linked to cognitive dysfunction. Thus, low-dose, intermittent, oral nCUR therapy has promise for improving brain function in veterans with GWI.
RESUMEN
Many animal prototypes illustrating the various attributes of human temporal lobe epilepsy (TLE) are available. These models have been invaluable for comprehending multiple epileptogenic processes, modifications in electrophysiological properties, neuronal hyperexcitability, neurodegeneration, neural plasticity, and chronic neuroinflammation in TLE. Some models have also uncovered the efficacy of new antiepileptic drugs or biologics for alleviating epileptogenesis, cognitive impairments, or spontaneous recurrent seizures (SRS). Nonetheless, the suitability of these models for testing candidate therapeutics in conditions such as chronic TLE is debatable because of a lower frequency of SRS and an inconsistent pattern of SRS activity over days, weeks or months. An ideal prototype of chronic TLE for investigating novel therapeutics would need to display a large number of SRS with a dependable frequency and severity and related co-morbidities. This study presents a new kainic acid (KA) model of chronic TLE generated through induction of status epilepticus (SE) in 6-8 weeks old male F344 rats. A rigorous characterization in the chronic epilepsy period validated that the animal prototype mimicked the most salient features of robust chronic TLE. Animals displayed a constant frequency and intensity of SRS across weeks and months in the 5th and 6th month after SE, as well as cognitive and mood impairments. Moreover, SRS frequency displayed a rhythmic pattern with 24-hour periodicity and a consistently higher number of SRS in the daylight period. Besides, the model showed many neuropathological features of chronic TLE, which include a partial loss of inhibitory interneurons, reduced neurogenesis with persistent aberrant migration of newly born neurons, chronic neuroinflammation typified by hypertrophied astrocytes and rod-shaped microglia, and a significant aberrant mossy fiber sprouting in the hippocampus. This consistent chronic seizure model is ideal for investigating the efficacy of various antiepileptic drugs and biologics as well as understanding multiple pathophysiological mechanisms underlying chronic epilepsy.