Long-term omega-3 supplementation modulates behavior, hippocampal fatty acid concentration, neuronal progenitor proliferation and central TNF-α expression in 7 month old unchallenged mice

Dietary polyunsaturated fatty acid (PUFA) manipulation is being investigated as a potential therapeutic supplement to reduce the risk of developing age-related cognitive decline (ARCD). Animal studies suggest that high omega (Ω)-3 and low Ω-6 dietary content reduces cognitive decline by decreasing central nervous system (CNS) inflammation and modifying neuroimmune activity. However, no previous studies have investigated the long term effects of Ω-3 and Ω-6 dietary levels in healthy aging mice leaving the important question about the preventive effects of Ω-3 and Ω-6 on behavior and underlying molecular pathways unaddressed. We aimed to investigate the efficacy of long-term Ω-3 and Ω-6 PUFA dietary supplementation in mature adult C57BL/6 mice. We measured the effect of low, medium and high Ω-3:Ω-6 dietary ratio, given from the age of 3 to 7 months, on anxiety and cognition-like behavior, hippocampal tissue expression of TNF-α, markers of neuronal progenitor proliferation and gliogenesis and serum cytokine concentration. Our results show that a higher Ω-3:Ω-6 PUFA diet ratio increased hippocampal PUFA, increased anxiety, improved hippocampal dependent spatial memory and reduced hippocampal TNF-α levels compared to a low Ω-3:Ω-6 diet. Furthermore, serum TNF-α concentration was reduced in the higher Ω-3:Ω-6 PUFA ratio supplementation group while expression of the neuronal progenitor proliferation markers KI67 and doublecortin (DCX) was increased in the dentate gyrus as opposed to the low Ω-3:Ω-6 group. Conversely, Ω-3:Ω-6 dietary PUFA ratio had no significant effect on astrocyte or microglia number or cell death in the dentate gyrus. These results suggest that supplementation of PUFAs may delay ageing effects on cognitive function in unchallenged mature adult C57BL/6 mice. This effect is possibly induced by increasing neuronal progenitor proliferation and reducing TNF-α

Inflammasomes in neuroinflammation and changes in brain function: a focused review

Recent literature has pointed to the existence of inflammasome-mediated inflammatory pathways in central nervous system disorders and associated changes in behavior. Neuroinflammation, which is an innate immune response in the central nervous system against harmful and irritable stimuli such as pathogens and metabolic toxic waste, as well as to chronic mild stress, is mediated by protein complexes known as inflammasomes. Inflammasomes activate pro-inflammatory caspases 1 and 5, which then cleave the precursor forms of pro-inflammatory cytokines IL-1β, IL-18 and IL-33 into their active forms. These pro-inflammatory cytokines have been shown to promote a variety of innate immune processes associated with infection, inflammation and autoimmunity, and thereby play an instrumental role in the instigation of neuroinflammation during old age and subsequent occurrence of neurodegenerative diseases, cognitive impairment and dementia. In particular, NLRP inflammasomes may also have a role in the etiologies of depression, Alzheimer’s disease and in metabolic disorders, such as Type II diabetes, obesity and cardiovascular diseases that have been shown to be co-morbid with psychiatric illnesses. It has been reported that while these inflammasomes may be activated through TNF-α dependent pathways, other cytokines, like IFN-γ, may assist in inhibiting their activation and thus delay disease progression. Furthermore some other cytokines, including IL-6, may not have a direct role in inflammasome-mediated diseases. An array of recent research suggests that NLRP inflammasomes targeted therapies could be used for alleviating neuroinflammation and for treatment of associated psychiatric illnesses, although this still remains a challenge and necessitates further extensive research. This review examines the complex inflammatory signaling pathways involved in the activation of NLRP inflammasomes and the role they play in promoting neuroinflammation and subsequent behavioral changes

The effect of long-term repeated exposure to 3,4-methylenedioxymethamphetamine on cardiovascular and thermoregulatory changes

Rationale3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") disrupts thermoregulation in rats and can lead to life-threatening hyperthermia in humans. MDMA administration can also lead to long-term neurotoxicity in animals and possibly humans.ObjectivesThe purpose of the current study was to extend previous results on the acute effects of MDMA on behavioral thermoregulation to a repeated dosing regime, simulating regular weekend use of ecstasy, on measures of thermoregulation and heart rate (HR).Materials and methodsSprague-Dawley rats with telemetry implants were administered 40 micromol/kg MDMA on three consecutive days each week for 1 or 6 weeks before being confined to an elevated ambient temperature (TA) (HOT; 30+/-1 degrees C) or an area at room temperature (ROOM; 21.5+/-1.5 degrees C) for 30 min. After the final drug administration, rats were placed in a thermal gradient for 4 h to allow behavioral thermoregulation.ResultsHOT rats showed higher core temperature (TC), HR, and locomotor activity than ROOM rats during confinement to a set TA (PConclusionLong-term treatment with MDMA resulted in apparent tolerance to the effects of the drug on HR, dysregulation of TC in thermal gradient, and depletion of cortical DOPAC and 5-HIAA.Emily Joy Jaehne, Abdallah Salem, Rodney James Irvin

Pharmacological and behavioral determinants of cocaine, methamphetamine, 3,4-methylenedioxymethamphetamine, and para -methoxyamphetamine-induced hyperthermia

The original publication is available at www.springerlink.comRationale: Cocaine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), and para-methoxyamphetamine (PMA) disrupt normal thermoregulation in humans, with PMA being associated with more severe cases of hyperthermia. Harm minimization advice on how to prevent overheating depends on appropriate thermoregulatory behavior by drug users. Objectives: The purpose of the current study was to establish dose–response relationships for the effects of a number of commonly used illicit stimulants and investigate the behavioral response to increased core temperature. Materials and methods Sprague-Dawley rats with telemetry implants were administered either saline or 4, 12, 26, 40 or 80 μmol/kg of cocaine, methamphetamine, MDMA, or PMA and confined to an ambient temperature of 30°C for 30 min, before being able to choose their preferred temperature on a thermally graded runway (11-41°C). Results: The increased core temperature caused by administration of cocaine, methamphetamine, and MDMA treatment led to the animals seeking the cool end of the runway to correct their core temperature, although this did not occur in PMA-treated rats. The order of potency for increasing core temperature was methamphetamine >PMA = MDMA> cocaine. This differed to the slopes of the dose–response curves where MDMA and PMA showed the steepest slope for the doses used followed by methamphetamine then cocaine. Conclusions: These results suggest that behavioral aspects of thermoregulation are important in assessing the potential of individual drugs to cause harmful increases in core temperature.Emily Joy Jaehne, Abdallah Salem and Rodney James Irvin