n-oleoylethanolamine and Cognition-Disorders

Brain is a site of diabetic end-organ damage. Diabetes-associated cognitive dysfunction, referred as "diabetic encephalopathy" (DE) has been coined for the patients with type 2 diabetes mellitus showing decline in their cognitive function, especially weak episodic memory, cognitive inflexibility and poor psychomotor performance leading towards Alzheimer's disease. Current evidence supported that aberrant synapses, energy metabolism imbalance, advanced glycation end products (AGEs) accumulation and Tau hyperphosphorylation are associated with cognition deficits induced by diabetes. Oleoylethanolamide (OEA), an endogenous peroxisome proliferator-activated receptor alpha (PPARα) agonist, has anti-hyperlipidemia, anti-inflammatory and neuroprotective activities. However, the effect of OEA on DE is unknown. Therefore, we tested its influence against cognitive dysfunction in high fat diet and streptozotocin (HFD + STZ)-induced diabetic C57BL/6J and PPARα

Topics: Animals; Blood Glucose; Brain Diseases; Cognition Disorders; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Endocannabinoids; Glycation End Products, Advanced; Hippocampus; Insulin Resistance; Lipids; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurogenesis; Neuronal Plasticity; Oleic Acids; PPAR alpha; Specific Pathogen-Free Organisms; Streptozocin; tau Proteins

Oleoylethanolamide (OEA) has been shown to have neuroprotective effects after acute cerebral ischemic injury. The aim of this study was to investigate the effects of chronic OEA treatment on ischemia-induced spatial cognitive impairments, electrophysiology behavior and hippocampal neurogenesis. Daily treatments of 30 mg/kg OEA significantly ameliorated spatial cognitive deficits and attenuated the inhibition of long-term potentiation (LTP) in the middle cerebral artery occlusion (MCAO) rat model. Moreover, OEA administration improved cognitive function in a manner associated with enhanced neurogenesis in the hippocampus. Further study demonstrated that treatment with OEA markedly increased the expressions of brain-derived neurotrophic factor (BDNF) and peroxisome proliferator-activated receptors α (PPARα). Our data suggest that chronic OEA treatment can exert functional recovery of cognitive impairments and neuroprotective effects against cerebral ischemic insult in rats via triggering of neurogenesis in the hippocampus, which supports the therapeutic use of OEA for cerebral ischemia.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cognition Disorders; Dentate Gyrus; Endocannabinoids; Hippocampus; Ischemic Attack, Transient; Long-Term Potentiation; Male; Maze Learning; Neurogenesis; Neuroglia; Neurons; Oleic Acids; PPAR alpha; Rats, Sprague-Dawley; Spatial Learning

MDMA (3,4-Methylenedioxymethamphetamine) is an amphetamine derivative widely used for recreational purposes. We have recently shown that repeated treatment with high doses of MDMA-induced impairments in the acquisition and recall of an active avoidance task in mice. In this study, we examined whether the endogenous peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist, oleoylethanolamide (OEA) protects against these MDMA-induced deficits. Mice were pretreated twice a day with OEA (0, 5, and 25 mg/kg) 30 min before an injection of MDMA (30 mg/kg) or saline during four consecutive days. Twenty-four hours after the last treatment, animals were trained in an active avoidance task for two consecutive weeks. After a 5-day resting period, a recall session was performed. Mice treated with MDMA showed reduced learning and recall of the task when compared with saline-treated controls. OEA at 5 mg/kg ameliorated and at 25 mg/kg worsened this deficit. Dopamine transporter (DAT)-binding sites significantly decreased 4 days after the last MDMA administration and pretreatment with both doses of OEA prevented this effect. In immunohistochemical studies, coexpression of tyrosine-hydroxylase and PPAR-alpha receptors was observed in the striatum and substantia nigra pars compacta of mice. These results suggest that OEA administration can modulate the cognitive deficits induced by MDMA in a DAT-independent manner.

Topics: Animals; Avoidance Learning; Cognition Disorders; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins; Dose-Response Relationship, Drug; Endocannabinoids; Hallucinogens; Male; Mental Recall; Mesencephalon; Mice; N-Methyl-3,4-methylenedioxyamphetamine; Nootropic Agents; Oleic Acids; PPAR alpha; Rats; Rats, Wistar; Substantia Nigra; Treatment Outcome; Tyrosine 3-Monooxygenase