Psychedelic 25H-NBOMe attenuates post-sepsis depression in rats.

Sepsis-associated encephalopathy, which manifests in severe cognitive and depressive symptoms, is directly linked to neuroinflammation. Our study investigates the efficacy of 25H-NBOMe, a phenethylamine, in alleviating these symptoms, potentially offering an innovative treatment for post-sepsis depression. Wistar rats, weighing between 250-300 g, were subjected to cecal ligation and puncture (CLP) surgery to induce sepsis. Depressive-like behaviors were assessed using the forced swim test (FST) on either day 7 or 14 post-surgery, to establish the presence of depressive symptoms. The impact of 25H-NBOMe treatment was then evaluated, focusing on the head-twitch response (HTR), performance in the FST, and GFAP expression in the prefrontal cortex. Treatment with 25H-NBOMe resulted in significant behavioral changes, demonstrated by decreased immobility and increased swimming times in the FST, along with a rise in the HTR. These outcomes indicate a reduction in depressive-like symptoms post-sepsis and the psychoactive effects of the compound. Furthermore, a notable decrease in GFAP expression in the study highlights the compound's impact on mitigating sepsis-induced astrogliosis. This study demonstrates the effectiveness of 25H-NBOMe, a psychedelic in the phenethylamine class, in treating post-sepsis depression and reducing astrogliosis. However, the psychedelic nature of 25H-NBOMe calls for further investigation into similar compounds with less psychoactive impact, crucial for advancing treatment options for neuropsychiatric symptoms following sepsis.

Design, synthesis, and biological evaluation of new thalidomide-donepezil hybrids as neuroprotective agents targeting cholinesterases and neuroinflammation.

A new series of eight multifunctional thalidomide-donepezil hybrids were synthesized based on the multi-target-directed ligand strategy and evaluated as potential neuroprotective, cholinesterase inhibitors and anti-neuroinflammatory agents against neurodegenerative diseases. A molecular hybridization approach was used for structural design by combining the N-benzylpiperidine pharmacophore of donepezil and the isoindoline-1,3-dione fragment from the thalidomide structure. The most promising compound, PQM-189 (3g), showed good AChE inhibitory activity with an IC50 value of 3.15 µM, which was predicted by docking studies as interacting with the enzyme in the same orientation observed in the AChE-donepezil complex and a similar profile of interaction. Additionally, compound 3g significantly decreased iNOS and IL-1ß levels by 43% and 39%, respectively, after 24 h of incubation with lipopolysaccharide. In vivo data confirmed the ability of 3g to prevent locomotor impairment and changes in feeding behavior elicited by lipopolysaccharide. Moreover, the PAMPA assay evidenced adequate blood-brain barrier and gastrointestinal tract permeabilities with an Fa value of 69.8%. Altogether, these biological data suggest that compound 3g can treat the inflammatory process and oxidative stress resulting from the overexpression of iNOS and therefore the increase in reactive nitrogen species, and regulate the release of pro-inflammatory cytokines such as IL-1ß. In this regard, compound PQM-189 (3g) was revealed to be a promising neuroprotective and anti-neuroinflammatory agent with an innovative thalidomide-donepezil-based hybrid molecular architecture.

Perinatal exposure to glyphosate-based herbicides induced neurodevelopmental behaviors impairments and increased oxidative stress in the prefrontal cortex and hippocampus in offspring.

Glyphosate is the organophosphate pesticide most widely used in the world. Recent studies correlate exposure to glyphosate and the emergence of neurodevelopmental disorders. Therefore, it was objective to propose a rat model of perinatal exposure to glyphosate-based herbicides (GBH) to study associated neurodevelopmental disorders. Behavioral aspects and brain pathways were assessed in the prepubertal phase. For this, maternal treatment occurred throughout the entire gestation period (from GD0) until weaning on postnatal day 22 (PND 22). Control group received oral gavage with 5 mL/kg of saline per day and GBH group received oral gavage with 50 mg/kg of GBH per day (n = 10 per group). Maternal behavior was evaluated in PND 2-6. Offspring were evaluated for quantification of ultrasonic vocalizations (PND 5); homing behavior test (PND 13); and hole board, social play behavior, open field, and object recognition tests (PND 28-32). Prefrontal cortex and hippocampus of the offspring were processed to evaluate oxidative stress. Maternal exposure to GBH impaired early social communication, olfactory discrimination, social play behavior, and the exploration of objects, in addition to increasing repetitive and stereotyped movements. GBH also increased oxidative stress. Therefore, perinatal GBH exposure induced behavioral and oxidative stress impairments in rats associated with neurodevelopmental disorders. The manifestations found in the offspring are in accordance with symptoms of autism spectrum disorder.

Maternal overweight induced by reduced litter size impairs the behavioral neurodevelopment of offspring.

AIMS: We assessed the influence of maternal overweight on the behavioral neurodevelopment of male and female offspring in prepubertal age by reducing the litter size. MAIN METHODS: To reduce litter size in Wistar rats, the offspring of generation 0 (G0) were culled for 12 pups (6 males and 6 females: normal litter, NL-G1) or 4 pups (2 males and 2 females: small litter, SL-G1). In G1 dams, overweight was characterized, maternal behavior and locomotor activity were assessed. At G2, we quantified the ultrasonic vocalizations in post-natal day 5 (PND5); we evaluated olfactory discrimination in the homing behavior test on PND13; and in PND28-32 (prepubertal age), we performed the following tests: social play behavior, hole board, object recognition, and open field. At the end of the experiments, hippocampus and prefrontal cortex were dissected to quantify the synaptophysin by western blotting. KEY FINDINGS: Our data demonstrated that a reduction in litter size was able to induce maternal overweight without altering the parameters related to overweight in the offspring. The SL-G2 offspring showed deficits in early social communication, olfactory discrimination, social play behavior, and the exploration of objects, in addition to increasing repetitive and stereotyped movements. There were also changes in the synaptophysin levels in the hippocampus and prefrontal cortex of the offspring from reduced litter dams. In conclusion, maternal overweight caused by litter reduction impairs behavioral neurodevelopment, inducing autism-like symptoms in the offspring. SIGNIFICANCE: This study alerts the public about the negative consequences of maternal overweight in the descendants.

Anxiety-like behavior and neuroendocrine changes in offspring resulting from gestational post-traumatic stress disorder.

Exposure to stressful environmental events during the perinatal period can increase vulnerability to psychopathologies that cause neuroendocrine changes associated with deficits in emotional behavior that can appear early in life. Post-traumatic stress disorder (PTSD) is a frequent, chronic, and disabling disorder that negatively impacts the emotional, social, and cognitive behaviors of affected individuals. Thus, we induced PTSD in pregnant rats by applying inescapable footshocks and then investigated the behavioral parameters similar to anxiety in offspring at prepubertal age, in addition to the plasma levels of maternal and offspring corticosterone and expression of glucocorticoid receptors (GR) in the offspring's hippocampus. With the dams, maternal behavior, open field, and object recognition tests were performed. With the male and female offspring, we performed the following: quantification of ultrasonic vocalizations, elevated plus-maze test, evaluation of exploratory activity in the open field, and hole board test, as well as plasma corticosterone measurements and Western blotting for GR. Our results showed that gestational PTSD affected maternal behavior, led to anxiety-like symptoms, increased corticosterone levels, and increased GR expression in the offspring's hippocampus. Therefore, our data can contribute to the understanding of the onset of early (childhood and juvenile/pre-pubertal phases) anxiety owing to exposure to a traumatic event during the gestation period.