Short-term long chain omega3 diet protects from neuroinflammatory processes and memory impairment in aged mice

Regular consumption of food enriched in omega3 polyunsaturated fatty acids (ω3 PUFAs) has been shown to reduce risk of cognitive decline in elderly, and possibly development of Alzheimer's disease. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are the most likely active components of ω3-rich PUFAs diets in the brain. We therefore hypothesized that exposing mice to a DHA and EPA enriched diet may reduce neuroinflammation and protect against memory impairment in aged mice. For this purpose, mice were exposed to a control diet throughout life and were further submitted to a diet enriched in EPA and DHA during 2 additional months. Cytokine expression together with a thorough analysis of astrocytes morphology assessed by a 3D reconstruction was measured in the hippocampus of young (3-month-old) and aged (22-month-old) mice. In addition, the effects of EPA and DHA on spatial memory and associated Fos activation in the hippocampus were assessed. We showed that a 2-month EPA/DHA treatment increased these long-chain ω3 PUFAs in the brain, prevented cytokines expression and astrocytes morphology changes in the hippocampus and restored spatial memory deficits and Fos-associated activation in the hippocampus of aged mice. Collectively, these data indicated that diet-induced accumulation of EPA and DHA in the brain protects against neuroinflammation and cognitive impairment linked to aging, further reinforcing the idea that increased EPA and DHA intake may provide protection to the brain of aged subjects.     

CD36 inhibitors reduce postprandial hypertriglyceridemia and protect against diabetic dyslipidemia and atherosclerosis

CD36 is recognized as a lipid and fatty acid receptor and plays an important role in the metabolic syndrome and associated cardiac events. The pleiotropic activity and the multiple molecular associations of this scavenger receptor with membrane associated molecules in different cells and tissues have however questioned its potential as a therapeutic target. The present study shows that it is possible to identify low molecular weight chemicals that can block the CD36 binding and uptake functions. These inhibitors were able to reduce arterial lipid deposition, fatty acid intestinal transit, plasma concentration of triglycerides and glucose, to improve insulin sensitivity, glucose tolerance and to reduce the plasma concentration of HbAc1 in different and independent rodent models. Correlation between the anti-CD36 activity of these inhibitors and the known pathophysiological activity of this scavenger receptor in the development of atherosclerosis and diabetes were observed at pharmacological doses. Thus, CD36 might represent an attractive therapeutic target.     

Denatured G-Protein Coupled Receptors as Immunogens to Generate Highly Specific Antibodies

G-protein coupled receptors (GPCRs) play a major role in a number of physiological and pathological processes. Thus, GPCRs have become the most frequent targets for development of new therapeutic drugs. In this context, the availability of highly specific antibodies may be decisive to obtain reliable findings on localization, function and medical relevance of GPCRs. However, the rapid and easy generation of highly selective anti-GPCR antibodies is still a challenge. Herein, we report that highly specific antibodies suitable for detection of GPCRs in native and unfolded forms can be elicited by immunizing animals against purified full length denatured recombinant GPCRs. Contrasting with the currently admitted postulate, our study shows that an active and well-folded GPCR is not required for the production of specific anti-GPCR antibodies. This new immunizing strategy validated with three different human GPCR (μ-opioid, κ-opioid, neuropeptide FF2 receptors) might be generalized to other members of the GPCR family.     

Early-life stress is associated with gender-based vulnerability to epileptogenesis in rat pups

During development, the risk of developing mesial temporal lobe epilepsy (MTLE) increases when the developing brain is exposed to more than one insult in early life. Early life insults include abnormalities of cortical development, hypoxic-ischemic injury and prolonged febrile seizures. To study epileptogenesis, we have developed a two-hit model of MTLE characterized by two early-life insults: a freeze lesion-induced cortical malformation at post-natal day 1 (P1), and a prolonged hyperthermic seizure (HS) at P10. As early life stressors lead to sexual dimorphism in both acute response and long-term outcome, we hypothesized that our model could lead to gender-based differences in acute stress response and long-term risk of developing MTLE. Male and female pups underwent a freeze-lesion induced cortical microgyrus at P1 and were exposed to HS at P10. Animals were monitored by video-EEG from P90 to P120. Pre and post-procedure plasma corticosterone levels were used to measure stress response at P1 and P10. To confirm the role of sex steroids, androgenized female pups received daily testosterone injections to the mother pre-natally and post-natally for nine days while undergoing both insults. We demonstrated that after both insults females did not develop MTLE while all males did. This correlated with a rise in corticosterone levels at P1 following the lesion in males only. Interestingly, all androgenized females showed a similar rise in corticosterone at P1, and also developed MTLE. Moreover, we found that the cortical lesion significantly decreased the latency to generalized convulsion during hyperthermia at P10 in both genders. The cortical dysplasia volumes at adulthood were also similar between male and female individuals. Our data demonstrate sexual dimorphism in long-term vulnerability to develop epilepsy in the lesion + hyperthermia animal model of MTLE and suggest that the response to early-life stress at P1 contributes significantly to epileptogenesis in a gender-specific manner.     

Dysregulation of Cytokine Response in Canadian First Nations Communities: Is There an Association with Persistent Organic Pollutant Levels?

In vitro and animal studies report that some persistent organic pollutants (POPs) trigger the secretion of proinflammatory cytokines. Whether POP exposure is associated with a dysregulation of cytokine response remains to be investigated in humans. We studied the strength of association between plasma POP levels and circulating cytokines as immune activation markers. Plasma levels of fourteen POPs and thirteen cytokines were measured in 39 Caucasians from a comparator sample in Québec City (Canada) and 72 First Nations individuals from two northern communities of Ontario (Canada). Caucasians showed significantly higher levels of organochlorine insecticides (β-HCH, p,p'-DDE and HCB) compared to First Nations. Conversely, First Nations showed higher levels of Mirex, Aroclor 1260, PCB 153, PCB 170, PCB 180 and PCB 187 compared to Caucasians. While there was no difference in cytokine levels of IL-4, IL-6, IL-10 and IL-22 between groups, First Nations had significantly greater average levels of IFNγ, IL-1β, IL-2, IL-5, IL-8, IL-12p70, IL-17A, TNFα and TNFβ levels compared to Caucasians. Among candidate predictor variables (age, body mass index, insulin resistance and POP levels), high levels of PCBs were the only predictor accounting for a small but significant effect of observed variance (～7%) in cytokine levels. Overall, a weak but significant association is detected between persistent organochlorine pollutant exposure and elevated cytokine levels. This finding augments the already existing information that environmental pollution is related to inflammation, a common feature of several metabolic disorders that are known to be especially prevalent in Canada's remote First Nations communities.     

Ranging behaviour of roe deer in an experimental high-density population: Are females territorial?

We studied the ranging behaviour and spatial relationships between seven roe deer during more than 4 years in a partly wooded 14.2-ha enclosure. The animals (three young males, four adult females) were monitored with GPS telemetry collars. As expected, the surface area and overlap of the males’ bimonthly ranges decreased, and the distance between their arithmetic centres increased, as they became adult and, for two of them, territorial. Unexpectedly, females also tended to space out, the surface area and overlap of their bimonthly ranges being minimal in May to June, i.e. during the birth period. The distance between their arithmetic centres reached its maximum at the same time. Overlap between females’ ranges was consistently lower than those between males and females’ ranges, or between 1-year old males’ ranges. Our results raise the questions of female seasonal territoriality and of independence of the spacing systems of the two sexes in roe deer.