domoic-acid and Cognition-Disorders

Our previous findings suggest that mitochondrial dysfunction is the mechanism underlying cognitive deficits induced by domoic acid (DA). Ursolic acid (UA), a natural triterpenoid compound, possesses many important biological functions. Evidence shows that UA can activate PI3K/Akt signaling and suppress Forkhead box protein O1 (FoxO1) activity. FoxO1 is an important regulator of mitochondrial function. Here we investigate whether FoxO1 is involved in the oxidative stress-induced mitochondrial dysfunction in DA-treated mice and whether UA inhibits DA-induced mitochondrial dysfunction and cognitive deficits through regulating the PI3K/Akt and FoxO1 signaling pathways. Our results showed that FoxO1 knockdown reversed the mitochondrial abnormalities and cognitive deficits induced by DA in mice through decreasing HO-1 expression. Mechanistically, FoxO1 activation was associated with oxidative stress-induced JNK activation and decrease of Akt phosphorylation. Moreover, UA attenuated the mitochondrial dysfunction and cognitive deficits through promoting Akt phosphorylation and FoxO1 nuclear exclusion in the hippocampus of DA-treated mice. LY294002, an inhibitor of PI3K/Akt signaling, significantly decreased Akt phosphorylation in the hippocampus of DA/UA mice, which weakened UA actions. These results suggest that UA could be recommended as a possible candidate for the prevention and therapy of cognitive deficits in excitotoxic brain disorders.

Topics: Animals; Animals, Genetically Modified; Cognition Disorders; Cyclooxygenase Inhibitors; Dependovirus; Fluorescent Antibody Technique; Forkhead Box Protein O1; Forkhead Transcription Factors; Genetic Vectors; Hippocampus; Kainic Acid; Male; Maze Learning; Mice; Mice, Inbred ICR; Mitochondrial Diseases; Neuromuscular Depolarizing Agents; Oncogene Protein v-akt; Oxidative Stress; Phosphatidylinositol 3-Kinases; Psychomotor Performance; Signal Transduction; Triterpenes; Ursolic Acid

Recent findings suggest that endoplasmic reticulum stress may be involved in the pathogenesis of domoic acid-induced neurodegeneration. Purple sweet potato color, a class of naturally occurring anthocyanins, has beneficial health and biological effects. Recent studies have also shown that anthocyanins have estrogenic activity and can enhance estrogen receptor-α expression. In this study, we evaluated the effect of purple sweet potato color on cognitive deficits induced by hippocampal mitochondrial dysfunction in domoic acid-treated mice and explored the potential mechanisms underlying this effect. Our results showed that the oral administration of purple sweet potato color to domoic acid-treated mice significantly improved their behavioral performance in a step-through passive avoidance task and a Morris water maze task. These improvements were mediated, at least in part, by a stimulation of estrogen receptor-α-mediated mitochondrial biogenesis signaling and by decreases in the expression of p47phox and gp91phox. Decreases in reactive oxygen species and protein carbonylation were also observed, along with a blockade of the endoplasmic reticulum stress pathway. Furthermore, purple sweet potato color significantly suppressed endoplasmic reticulum stress-induced apoptosis, which prevented neuron loss and restored the expression of memory-related proteins. However, knockdown of estrogen receptor-α using short hairpin RNA only partially blocked the neuroprotective effects of purple sweet potato color in the hippocampus of mice cotreated with purple sweet potato color and domoic acid, indicating that purple sweet potato color acts through multiple pathways. These results suggest that purple sweet potato color could be a possible candidate for the prevention and treatment of cognitive deficits in excitotoxic and other brain disorders.

Topics: Animals; Anthocyanins; Apoptosis; Catalase; Cognition Disorders; Endoplasmic Reticulum Stress; Estrogen Receptor alpha; Hippocampus; Ipomoea batatas; Kainic Acid; Male; Maze Learning; Mice; Mice, Inbred ICR; Mitochondria; NADPH Oxidases; Neurodegenerative Diseases; Neuroprotective Agents; Nuclear Respiratory Factor 1; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Plant Extracts; Reactive Oxygen Species; Signal Transduction; Superoxide Dismutase; Superoxide Dismutase-1; Trans-Activators; Transcription Factors; Up-Regulation

Accumulated evidence indicates that domoic acid (DA)-induced excitatory neuronal injury is associated with excessive reactive oxygen species (ROS) production. Protein kinase C zeta (PKC-ζ)/nicotinamide adenine dinucleotide phosphate (NOX) signaling regulates ROS levels and is involved in various neurodegenerative disorders including excitoneurotoxicity. Our previous studies have demonstrated that ROS-induced activation of the stress-activated protein kinase/c-jun-N-terminal kinase (SAPK/JNK) pathway plays a key role in the pathogenesis of cognitive deficits induced by DA. However, the precise biological mechanisms underlying these effects are not well understood. In this study, we investigate whether the PKC-ζ mediates DA-induced cognitive deficits and further explored the potential molecular processes. DA treatment significantly increased the expression of PI3K p85α, and PKC-ζ in the hippocampus of mice, which promoted the p47phox phosphorylation and expression, enhanced NOX activity, and increased the levels of ROS and protein carbonyls. In turn, the abnormal ROS levels in the hippocampus of DA-treated mice activated SAPK/JNK pathway, decreased FoxO1 phosphorylation, stimulated the nuclear translocation of FoxO1, activated FasL/Fas signaling, and promoted the activation of caspase-8 and caspase-3, which resulted in neuron apoptosis and cognitive deficits in mice. However, PKC-ζ knockdown reversed these changes in mice. It was further demonstrated that FoxO1 was a downstream target of SAPK/JNK signaling by FoxO1 small interfering RNA and SP600125 (an inhibitor of SAPK/JNK pathway) treatment. Additionally, SP600125 treatment or FoxO1 knockdown also blocked FasL/Fas signaling-dependent apoptosis and improved DA-induced cognitive deficits in the hippocampus of mice. These results suggest that PKC-ζ could be a possible target for the prevention or treatment of cognitive deficits in excitotoxic and other brain disorders.

Topics: Animals; Base Sequence; Behavior, Animal; Cognition Disorders; DNA Primers; Gene Knockdown Techniques; Kainic Acid; Male; Mice; Mice, Inbred ICR; Protein Kinase C; RNA, Small Interfering

Topics: Animals; Cognition Disorders; Eutrophication; Female; Fisheries; Food Contamination; Humans; Kainic Acid; Neuromuscular Depolarizing Agents; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Risk Assessment; Shellfish