The role of glial cells in mental illness: a systematic review on astroglia and microglia as potential players in schizophrenia and its cognitive and emotional aspects

Schizophrenia is a complex and severe mental disorder that affects approximately 1% of the global population. It is characterized by a wide range of symptoms, including delusions, hallucinations, disorganized speech and behavior, and cognitive impairment. Recent research has suggested that the immune system dysregulation may play a significant role in the pathogenesis of schizophrenia, and glial cells, such as astroglia and microglia known to be involved in neuroinflammation and immune regulation, have emerged as potential players in this process. The aim of this systematic review is to summarize the glial hallmarks of schizophrenia, choosing as cellular candidate the astroglia and microglia, and focusing also on disease-associated psychological (cognitive and emotional) changes. We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched PubMed, Scopus, and Web of Science for articles that investigated the differences in astroglia and microglia in patients with schizophrenia, published in the last 5 years. The present systematic review indicates that changes in the density, morphology, and functioning of astroglia and microglia may be involved in the development of schizophrenia. The glial alterations may contribute to the pathogenesis of schizophrenia by dysregulating neurotransmission and immune responses, worsening cognitive capabilities. The complex interplay of astroglial and microglial activation, genetic/epigenetic variations, and cognitive assessments underscores the intricate relationship between biological mechanisms, symptomatology, and cognitive functioning in schizophrenia

n-3 PUFA improves psychological well-being during menopausal transition

Females show an increased risk of cognitive impairment when approaching menopause because of the loss of ovarian function and estrogen deficiency occurring during the climacteric. In addition, menopause is closely associated with emotional disorders, such as anxiety and depression. Data on risk and protection factors have yielded robust evidence on the effects of lifestyle factors, such as diet, in preserving emotional and cognitive functioning. The impact of specific lifestyle factors on psychological health indicates that there may be potential to improve (or at least stabilise) declining trajectories of emotional and cognitive functions in menopause. This work focused on the effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) supplementation on cognitive functions, depression and anxiety during the menopausal transition. This systematic review, performed according to PRISMA guidelines, considered all articles published until December 31st 2021 and the search was performed on two databases, PUBMED and SCOPUS. The fields of interest were “menopausal transition”, “n-3 PUFA” and “cognitive and affective aspects”. Out of the 361 articles found on PUBMED and 283 on Scopus, 17 met the inclusion criteria. They encompassed 11 human and 6 experimental studies. Most clinical and preclinical studies report relieved depressive symptoms in relation to n-3 PUFA intake in menopause. Controversial results have been found in menopausal women on anxiety and cognitive functions, while in the few studies carried out in animal models n-3 PUFA reduced anxiety symptoms and improved cognitive functions. Taken together, the current results show beneficial effects of n-3 PUFA on emotional and cognitive behaviours during menopause transition. However, further investigations should be performed to increase knowledge about the real effectiveness of n-3 PUFA on psychological well-being in this delicate period of feminine life

Behavioral effects of long-term administration of palmitoylethanolamide on Tg2576 mice

Aim: To date, pharmacological approaches to treat dementia and particularly Alzheimer disease (AD) remain uncertain and unclear. In this context, palmitoylethanolamide (PEA) has been emerging as an important analgesic, anti-inflammatory and neuroprotective mediator, acting at several molecular targets in both central and peripheral nervous systems as well as immune cells, and has demonstrated high safety and tolerability. PEA is present in certain foods we use every day such as egg yolk, corn, peanut and soy oils and is also produced by many cells in our organism. It can be found in high concentrations in brain tissues and is synthesized starting by lipid components of the cellular membranes. In the present study, we sought to investigate the behavioral modifications potentially induced by a chronic administration of ultra-micronized PEA (i.e., a micrometer-sized crystalline form that improves both its pharmacokinetics and bioavailability) for 6-months in transgenic mice expressing mutant APP (Tg2576 mice). These mice express high levels of mutated human APP and with advancing age develop both amyloid peptide accumulation and amyloid plaques in the brain, as well as behavioral and cognitive deficits; thus, they represent a widely accepted animal model of AD. Methods: The 6-month administration of PEA in Tg2576 mice and the wild-type (WT) control group was via a subcutaneous (s.c.) delivery system. Mice were subjected to s.c. implantation of PEA or placebo pellets at 6 months of age. PEA effects on motor, cognitive and emotional performances were monitored longitudinally, by a battery of behavioral tasks, within three different ages, corresponding to a pre-symptomatic phase (T0 = 3 months), a mild-symptomatic phase (T1 = 6.5 months) and a fully symptomatic phase (T2 = 11-12 months; ie., at the end of the chronic supplementation). All mice underwent the behavioral assessment by using the following battery of validated tests: Elevated Plus Maze (EPM), to assess anxiety levels and locomotor skills; Rotarod Test (RT), to assess motor coordination skills; Y-Maze Spontaneous Alternation Test (Y-Maze), to assess working memory skills; Novel Object Recognition Test (NORT), to assess mnestic and discriminative skills; Tail Suspension Test (TST), to assess depressive behaviors. Results: Behavioral analyses performed on our mice demonstrate that chronic PEA supplementation exerts beneficial effects on NORT mnesic performances of Tg2576 mice at T2. Specifically, in Tg2576 mice chronic PEA supplementation restored the novelty recognition memory impaired during the fully symptomatic phase, while did not affect working memory, motor coordination, anxiety, and depressive-like alterations. No PEA effects were observed in WT mice. Conclusions: PEA is able to counteract specific hippocampal-dependent mnesic deficits typical of AD. Our data suggest the likely therapeutic potential of ultra-micronized PEA as an early treatment in AD. These findings should be further investigated to increase knowledge of the effects of PEA as a safe and low-cost nutraceutical tool useful to improve quality of life in AD

n-3 PUFA Improve Emotion and Cognition during Menopause: A Systematic Review

Women show an increased risk of cognitive impairment and emotional disorders, such as anxiety and depression, when approaching menopause. Data on risk and protection factors have yielded robust evidence on the effects of lifestyle factors, such as diet, in preserving emotional and cognitive functioning. This review focused on the effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) on anxiety, depression, and cognition during the menopausal transition. This systematic review considered all articles published until 31 December 2021, and the search was performed on two databases, PubMed and Scopus. The fields of interest were “menopause”, “n-3 PUFA” and “emotional and cognitive aspects”. Out of the 361 articles found on PubMed and 283 on Scopus, 17 met inclusion criteria. They encompassed 11 human and 6 animal studies. Most studies reported relieved depressive symptoms in relation to n-3 PUFA intake. While controversial results were found on anxiety and cognition in humans, n-3 PUFA consistently reduced anxiety symptoms and improved cognition in animal studies. Taken together, n-3 PUFA intake shows beneficial effects on emotional and cognitive behaviours during menopause transition. However, further investigations could increase knowledge about the effectiveness of n-3 PUFA on psychological well-being in this delicate period of feminine life

Chronic administration of palmitoylethanolamide counteracts cognitive decline in Tg2576 Mice

Palmitoylethanolamide (PEA) has been emerging as a safe and well tolerated analgesic, anti-inflammatory and neuroprotective mediator, acting at several molecular targets in the nervous system. PEA is present in foods, as egg yolk, corn, peanut and soy oil. It is synthesized from lipid components of cellular membranes and can be found in high concentrations in brain tissues. In this study, we evaluated the effects of a chronic (6 months) administration of ultra-micronized PEA on cognitive decline in transgenic Tg2576 (Tg) mice expressing mutant APP. When aged, Tg mice develop accumulation of amyloid peptide and amyloid plaques in the brain, as well as cognitive deficits, representing thus an animal model of AD. PEA administration was performed via a subcutaneous delivery system in Tg mice and wild-type control group (from 6 to 12 months of age). PEA effects on behavior were observed longitudinally in a pre-symptomatic phase (3 months), a mild-symptomatic phase (6.5 months) and a full-symptomatic phase (11-12 months). Behavioral assessment was performed by using the following validated tests: Elevated Plus Maze, Rotarod Test, Y-Maze Spontaneous Alternation Test, Novel Object Recognition Test, Tail Suspension Test and Morris Water Maze. PEA administration restored the novelty recognition memory of Tg mice during the full-symptomatic phase. PEA was able to counteract hippocampal- dependent mnesic deficits, suggesting the therapeutic potential for the early treatment of AD. Further in progress analyses involve histological evaluation of dendritic branching, spine number, amyloid plaques and glial reactivity in the hippocampal CA1. This research is aimed to increase knowledge of the effects of PEA as a safe and low-cost nutraceutical tool useful to improve quality of life in AD

Specialized pro-resolving mediator RvD1 reduces neuroinflammation in a transgenic rat model of Parkinson’s disease

The neuroinflammatory processes in Parkinson’s disease (PD) are usually associated with activation of the immune system caused by a growing aggregation of α-synuclein (α-Syn) in central nervous system. The active immune response in brain of PD patients leads to infiltration of lymphocytes, production of cytokines and microgliosis, these features could be a consequence of failure to resolve inflammation, a process mediated by a superfamily of endogenous lipids termed specialized pro-resolvin mediators (SPMs). A previous study from our group has shown that precocious treatment with resolvin D1 (RvD1) prevents the onset of PD by attenuating immune response in a rat model of PD. Herein, we explored the long-term effect of RvD1 in α-Syn rats by treating them with intraperitoneal injections twice a week, starting at early stage of the disease (2 months old) until the symptomatic phase (12 months old). Hence, we assessed motor deficit evaluated through Rotarod test and the infiltration of the main CD45+ leukocyte cell populations (i.e. CD3+ T-cells, CD45RA+ B-cells, CD161+ NK-cells and CD45/CD11bhigh macrophages) within substantia nigra and striatum by flow cytometry. We found that α-Syn rats showed a higher degree of nigral and striatal infiltration of all cell subsets compared to age-matched wildtype rats and that RvD1 treatment not only ameliorated motor deficits but also reduced their infiltration in both anatomical regions. Furthermore, although the percentage of CD45lowCD11b+ microglial cells remained unchanged between the different experimental groups, we observed that microglia of α-Syn rats shifted from a pro-inflammatory M1-like to a pro-resolving/anti-inflammatory M2-like immunophenotype upon RvD1 treatment, in terms of modulation of their respective M1 (CD68, CD86, MHC-II) and M2 (CD206, TREM2) markers. These results suggest that RvD1 is able to delay disease progression by blunting neuroinflammation and inducing a microglia- driven pro-resolving response

Neuroprotective role of dietary supplementation with Omega-3 fatty acids in the presence of basal forebrain cholinergic neurons degeneration in aged mice

As major components of neuronal membranes, omega-3 polyunsaturated fatty acids (n-3 PUFA) exhibit a wide range of regulatory functions. Recent human and animal studies indicate that n-3 PUFA may exert beneficial effects on aging processes. Here we analyzed the neuroprotective influence of n-3 PUFA supplementation on behavioral deficits, hippocampal neurogenesis, volume loss, and astrogliosis in aged mice that underwent a selective depletion of basal forebrain cholinergic neurons. Such a lesion represents a valid model to mimic a key component of the cognitive deficits associated with dementia. Aged mice were supplemented with n-3 PUFA or olive oil (as isocaloric control) for 8 weeks and then cholinergically depleted with mu-p75-saporin immunotoxin. Two weeks after lesioning, mice were behaviorally tested to assess anxious, motivational, social, mnesic, and depressive-like behaviors. Subsequently, morphological and biochemical analyses were performed. In lesioned aged mice the n-3 PUFA pre-treatment preserved explorative skills and associative retention memory, enhanced neurogenesis in the dentate gyrus, and reduced volume and VAChT levels loss as well as astrogliosis in hippocampus. The present findings demonstrating that n-3 PUFA supplementation before cholinergic depletion can counteract behavioral deficits and hippocampal neurodegeneration in aged mice advance a low-cost, non-invasive preventive tool to enhance life quality during aging

Correction: Cutuli et al. Neuroprotective Role of Dietary Supplementation with Omega-3 Fatty Acids in the Presence of Basal Forebrain Cholinergic Neurons Degeneration in Aged Mice. Int. J. Mol. Sci. 2020, 21, 1741

The authors wish to make the following corrections to this paper [...