Amygdalar neurotransmission alterations in the BTBR mice model of idiopathic autism.

Autism Spectrum Disorders (ASD) are principally diagnosed by three core behavioural symptoms, such as stereotyped repertoire, communication impairments and social dysfunctions. This complex pathology has been linked to abnormalities of corticostriatal and limbic circuits. Despite experimental efforts in elucidating the molecular mechanisms behind these abnormalities, a clear etiopathogenic hypothesis is still lacking. To this aim, preclinical studies can be really helpful to longitudinally study behavioural alterations resembling human symptoms and to investigate the underlying neurobiological correlates. In this regard, the BTBR T+ Itpr3tf/J (BTBR) mice are an inbred mouse strain that exhibits a pattern of behaviours well resembling human ASD-like behavioural features. In this study, the BTBR mice model was used to investigate neurochemical and biomolecular alterations, regarding Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), together with GABAergic, glutamatergic, cholinergic, dopaminergic and noradrenergic neurotransmissions and their metabolites in four different brain areas, i.e. prefrontal cortex, hippocampus, amygdala and hypothalamus. In our results, BTBR strain reported decreased noradrenaline, acetylcholine and GABA levels in prefrontal cortex, while hippocampal measurements showed reduced NGF and BDNF expression levels, together with GABA levels. Concerning hypothalamus, no differences were retrieved. As regarding amygdala, we found reduced dopamine levels, accompanied by increased dopamine metabolites in BTBR mice, together with decreased acetylcholine, NGF and GABA levels and enhanced glutamate content. Taken together, our data showed that the BTBR ASD model, beyond its face validity, is a useful tool to untangle neurotransmission alterations that could be underpinned to the heterogeneous ASD-like behaviours, highlighting the crucial role played by amygdala.

Increased stress vulnerability in the offspring of socially isolated rats: Behavioural, neurochemical and redox dysfunctions.

Stressful events during pregnancy impact on the progeny neurodevelopment. However, little is known about preconceptional stress effects. The rat social isolation represents an animal model of chronic stress inducing a variety of dysfunctions. Moreover, social deprivation during adolescence interferes with key neurodevelopmental processes. Here, we investigated the development of behavioural, neurochemical and redox alterations in the male offspring of socially isolated female rats before pregnancy, reared in group (GRP) or in social isolation (ISO) from weaning until young-adulthood. To this aim, females were reared in GRP or in ISO conditions, from PND21 to PND70, when they were mated. Their male offspring was housed in GRP or ISO conditions through adolescence and until PND70, when passive avoidance-PA, novel object recognition-NOR and open field-OF tests were performed. Levels of noradrenaline (NA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), glutamate (GLU) and GABA were assessed in the prefrontal cortex (PFC). Moreover, cortical ROS levels were quantified, as well as NF-kB and the NADPH oxidase NOX2 expression, redox status (expressed as GSH:GSSG ratio) and SOD1 amount. A significant decrease of the latency time in the PA was observed in the offspring of ISO females. In the NOR test, while a significant increase in the exploratory activity towards the novel object was observed in the offspring of GRP females, no significant differences were found in the offspring of ISO females. No significant differences were found in the OF test among experimental groups. Theoffspring of ISO females showed increased NA and 5-HIAA levels, whereas in the offspring persistently housed in isolation condition from weaninguntil adulthood, we detected reduced 5-HT levels and ehnanced 5-HIAA amount. No significant changes in GLU concentrations were detected, while decreased GABA content was observed in the offspring of ISO females exposed to social isolation. Increased ROS levels as well as reduced NF-κB, NOX2 expression were detected in the offspring of ISO females. This was accompanied by reduced redox status and enhanced SOD1 levels. In conclusion, our results suggest that female exposure to chronic social stress before pregnancy might have a profound influence on the offspring neurodevelopment in terms of cognitive, neurochemical and redox-related alterations, identifying this specific time window for possible preventive and therapeutic strategies.

Radiosynthesis and whole-body distribution in mice of a 18 F-labeled azepino[4,3-b]indole-1-one derivative with multimodal activity for the treatment of Alzheimer's disease.

Recently, the azepino[4,3-b]indole-1-one derivative 1 showed in vitro nanomolar inhibition against butyrylcholinesterase (BChE), the ChE isoform that plays a role in the progression and pathophysiology of Alzheimer's disease (AD), and protects against N-methyl- d-aspartate-induced neuronal toxicity. Three 9-R-substituted (R = F, Br, OMe) congeners were investigated. The 9-F derivative (2a) was found more potent as BChE inhibitors (half-maximal inhibitory concentration value = 21 nM) than 2b (9-Br) and 2c (9-OMe), achieving a residence time (38 s), assessed by surface plasmon resonance, threefold higher than that of 1. To progress in featuring the in vivo pharmacological characterization of 2a, herein the 18 F-labeled congener 2a was synthesized, by applying the aromatic 18 F-fluorination method, and its whole-body distribution in healthy mice, including brain penetration, was evaluated through positron emission tomography imaging. [18 F]2a exhibited a rapid and high brain uptake (3.35 ± 0.26% ID g-1 at 0.95 ± 0.15 min after injection), followed by a rapid clearance (t1/2 = 6.50 ± 0.93 min), showing good blood-brain barrier crossing. After a transient liver accumulation of [18 F]2a, the intestinal and urinary excretion was quantified. Finally, ex vivo pharmacological experiments in mice showed that the unlabeled 2a affects the transmitters' neurochemistry, which might be favorable to reverse cognition impairment in mild-to-moderate AD-related dementias.

Sex-oriented perspectives in immunopharmacology.

Several immunopharmacological agents are effective in the treatment of cancer and immune-mediated conditions, with a favorable impact on life expectancy and clinical outcomes for a large number of patients. Nevertheless, response variation and undesirable effects of these drugs represent major issues, and overall efficacy remains unpredictable. Males and females show a distinct difference in immune system responses, with females generally mounting stronger responses to a variety of stimuli. Therefore, exploring sex differences in the efficacy and safety of immunopharmacological agents would strengthen the practice of precision medicine. As a pharmacological target highlight, programmed cell death 1 ligand 1 (PD-L1) is the first functionally characterized ligand of the coinhibitory programmed death receptor 1 (PD-1). The PD-L1/PD-1 crosstalk plays an important role in the immune response and is relevant in cancer, infectious and autoimmune disease. Sex differences in the response to immune checkpoint inhibitors are well documented, with male patients responding better than female patients. Similarly, higher efficacy of and adherence to tumor necrosis factor inhibitors in chronic inflammatory conditions including rheumatoid arthritis and Crohn's disease have been reported in male patients. The pharmacological basis of sex-specific responses to immune system modulating drugs is actively investigated in other settings such as stroke and type 1 diabetes. Advances in therapeutics targeting the endothelium could soon be wielded against autoimmunity and metabolic disorders. Based on the established sexual dimorphism in immune-related pathophysiology and disease presentation, sex-specific immunopharmacological protocols should be integrated into clinical guidelines.

Palmitoylethanolamide counteracts high-fat diet-induced gut dysfunction by reprogramming microbiota composition and affecting tryptophan metabolism.

Obesity is associated with gastrointestinal (GI) tract and central nervous system (CNS) disorders. High-fat diet (HFD) feeding-induced obesity in mice induces dysbiosis, causing a shift toward bacteria-derived metabolites with detrimental effects on metabolism and inflammation: events often contributing to the onset and progression of both GI and CNS disorders. Palmitoylethanolamide (PEA) is an endogenous lipid mediator with beneficial effects in mouse models of GI and CNS disorders. However, the mechanisms underlining its enteroprotective and neuroprotective effects still need to be fully understood. Here, we aimed to study the effects of PEA on intestinal inflammation and microbiota alterations resulting from lipid overnutrition. Ultramicronized PEA (30 mg/kg/die per os) was administered to HFD-fed mice for 7 weeks starting at the 12th week of HFD regimen. At the termination of the study, the effects of PEA on inflammatory factors and cells, gut microbial features and tryptophan (TRP)-kynurenine metabolism were evaluated. PEA regulates the crosstalk between the host immune system and gut microbiota via rebalancing colonic TRP metabolites. PEA treatment reduced intestinal immune cell recruitment, inflammatory response triggered by HFD feeding, and corticotropin-releasing hormone levels. In particular, PEA modulated HFD-altered TRP metabolism in the colon, rebalancing serotonin (5-HT) turnover and reducing kynurenine levels. These effects were associated with a reshaping of gut microbiota composition through increased butyrate-promoting/producing bacteria, such as Bifidobacterium, Oscillospiraceae and Turicibacter sanguinis, with the latter also described as 5-HT sensor. These data indicate that the rebuilding of gut microbiota following PEA supplementation promotes host 5-HT biosynthesis, which is crucial in regulating intestinal function.

The Oncogenic Theory of Preeclampsia: Is Amniotic Mesenchymal Stem Cells-Derived PLAC1 Involved?

The pathomechanisms of preeclampsia (PE), a complication of late pregnancy characterized by hypertension and proteinuria, and due to improper placentation, are not well known. Mesenchymal stem cells derived from the amniotic membrane (AMSCs) may play a role in PE pathogenesis as placental homeostasis regulators. PLACenta-specific protein 1 (PLAC1) is a transmembrane antigen involved in trophoblast proliferation that is found to be associated with cancer progression. We studied PLAC1 in human AMSCs obtained from control subjects (n = 4) and PE patients (n = 7), measuring the levels of mRNA expression (RT-PCR) and secreted protein (ELISA on conditioned medium). Lower levels of PLAC1 mRNA expression were observed in PE AMSCs as compared with Caco2 cells (positive controls), but not in non-PE AMSCs. PLAC1 antigen was detectable in conditioned medium obtained from PE AMSCs, whereas it was undetectable in that obtained from non-PE AMSCs. Our data suggest that abnormal shedding of PLAC1 from AMSC plasma membranes, likely by metalloproteinases, may contribute to trophoblast proliferation, supporting its role in the oncogenic theory of PE.

Social isolation from early life induces anxiety-like behaviors in adult rats: Relation to neuroendocrine and neurochemical dysfunctions.

Subjects suffering from psychosis frequently experience anxiety. However, mechanisms underlying this comorbidity remain still unclear. We investigated whether neurochemical and neuroendocrine dysfunctions were involved in the development of anxiety-like behavior in a rodent model of psychotic-like symptoms, obtained by exposing male rats to social isolation rearing from postnatal day 21 to postnatal day 70. In the elevated zero maze test, isolated rats showed a significant reduction in the time spent in the open arms, as well as an increase in the time spent in the closed arms, compared to controls. An increased grooming time in the open field test was also observed in isolated animals. Isolation-induced anxiety-like behavior was accompanied by a decrease of plasmatic oxytocin, prolactin, ghrelin and melatonin levels, whereas plasmatic amount of Neuropeptide S was not altered. Social isolation also caused a reduction of noradrenaline, serotonin and GABA levels, together with an increase of serotonin turnover and glutamate levels in the amygdala of isolated animals. No significant differences were found in noradrenaline and serotonin levels, as well as in serotonin turnover in hippocampus, while glutamate amount was increased and GABA levels were reduced in isolated rats. Furthermore, there was a reduction in plasmatic serotonin content, and an increase in plasmatic kynurenine levels following social isolation, while no significant changes in serotonin turnover were observed. Taken together, our data provide novel insights in the neurobiological alterations underlying the comorbidity between psychosis and anxiety, and open new perspectives for multi-target therapies acting on both neurochemical and neuroendocrine pathways. DATA AVAILABILITY STATEMENT: The data presented in this study are available on request from the corresponding author.

Glucoraphanin Triggers Rapid Antidepressant Responses in a Rat Model of Beta Amyloid-Induced Depressive-like Behaviour.

Glucoraphanin (GRA) is a natural compound that has shown beneficial effects in chronic diseases and in central nervous system disorders. Moreover, GRA displayed antidepressant activity in preclinical models. We have previously demonstrated that a single intracerebroventricular administration of soluble amyloid-beta 1-42 (sAß 1-42) in rat evokes a depressive-like phenotype by increasing immobility frequency in the forced swimming test (FST). The aim of this work was to investigate the effect of GRA in naïve and in sAß-1-42-treated rats by using the FST. Behavioural analyses were accompanied by neurochemical and biochemical measurements in the prefrontal cortex (PFC), such as serotonin (5-HT), noradrenaline (NA), kynurenine (KYN), tryptophan (TRP), reactive oxygen species (ROS) and the transcription nuclear factor kappa B (NF-kB) levels. We reported that GRA administration in naïve rats at the dose of 50 mg/kg reduced the immobility frequency in the FST and increased 5-HT and NA levels in the PFC compared to controls. At the same dose, GRA reverted depressive-like effects of sAß 1-42 administration, restored the 5-HT levels and reduced NF-kB, KYN and ROS levels in PFC. In conclusion, GRA rapidly reverting depressive-like behaviour, together with biochemical and neurochemical alterations, might represent a safe and natural candidate for the treatment of depression.

Ketamine administration in early postnatal life as a tool for mimicking Autism Spectrum Disorders core symptoms.

Autism Spectrum Disorders (ASD) core symptoms include deficits of social interaction, stereotyped behaviours, dysfunction in language and communication. Beyond them, several additional symptoms, such as cognitive impairment, anxiety-like states and hyperactivity are often occurring, mainly overlapping with other neuropsychiatric diseases. To untangle mechanisms underlying ASD etiology, and to identify possible pharmacological approaches, different factors, such as environmental, immunological and genetic ones, need to be considered. In this context, ASD animal models, aiming to reproduce the wide range of behavioural phenotypes of this uniquely human disorder, represent a very useful tool. Ketamine administration in early postnatal life of mice has already been studied as a suitable animal model resembling psychotic-like symptoms. Here, we investigated whether ketamine administration, at postnatal days 7, 9 and 11, might induce behavioural features able to mimic ASD typical symptoms in adult mice. To this aim, we developed a 4-days behavioural tests battery, including Marble Burying, Hole Board, Olfactory and Social tests, to assess repetitive and stereotyped behaviour, social deficits and anxiety-like symptoms. Moreover, by using this mouse model, we performed neurochemical and biomolecular analyses, quantifying neurotransmitters belonging to excitatory-inhibitory pathways, such as glutamate, glutamine and gamma-aminobutyric acid (GABA), as well as immune activation biomarkers related to ASD, such as CD11b and glial fibrillary acidic protein (GFAP), in the hippocampus and amygdala. Possible alterations in levels of brain-derived neurotrophic factor (BDNF) expression in the hippocampus and amygdala were also evaluated. Our results showed an increase in stereotyped behaviours, together with social impairments and anxiety-like behaviour in adult mice, receiving ketamine administration in early postnatal life. In addition, we found decreased BDNF and enhanced GFAP hippocampal expression levels, accompanied by elevations in glutamate amount, as well as reduction in GABA content in amygdala and hippocampus. In conclusion, early ketamine administration may represent a suitable animal model of ASD, exhibiting face validity to mimic specific ASD symptoms, such as social deficits, repetitive repertoire and anxiety-like behaviour.

SARS-CoV-2 Gamma and Delta Variants of Concern Might Undermine Neutralizing Activity Generated in Response to BNT162b2 mRNA Vaccination.

The Delta variant raised concern regarding its ability to evade SARS-CoV-2 vaccines. We evaluated a serum neutralizing response of 172 Italian healthcare workers, three months after complete Comirnaty (BNT162b2 mRNA, BioNTech-Pfizer) vaccination, testing their sera against viral isolates of Alpha, Gamma and Delta variants, including 36 subjects with a previous SARS-CoV-2 infection. We assessed whether IgG anti-spike TRIM levels and serum neutralizing activity by seroneutralization assay were associated. Concerning Gamma variant, a two-fold reduction in neutralizing titres compared to the Alpha variant was observed, while a four-fold reduction of Delta virus compared to Alpha was found. A gender difference was observed in neutralizing titres only for the Gamma variant. The serum samples of 36 previously infected SARS-CoV-2 individuals neutralized Alpha, Gamma and Delta variants, demonstrating respectively a nearly three-fold and a five-fold reduction in neutralizing titres compared to Alpha variant. IgG anti-spike TRIM levels were positively correlated with serum neutralizing titres against the three variants. The Comirnaty vaccine provides sustained neutralizing antibody activity towards the Alpha variant, but it is less effective against Gamma and even less against Delta variants.

Social isolation triggers oxidative status and impairs systemic and hepatic insulin sensitivity in normoglycemic rats.

Drug-naïve psychotic patients show metabolic and hepatic dysfunctions. The rat social isolation model of psychosis allows to investigate mechanisms leading to these disturbances to which oxidative stress crucially contributes. Here, we investigated isolation-induced central and peripheral dysfunctions in glucose homeostasis and insulin sensitivity, along with redox dysregulation. Social isolation did not affect basal glycemic levels and the response to glucose and insulin loads in the glucose and insulin tolerance tests. However, HOMA-Index value were increased in isolated (ISO) rats. A hypothalamic reduction of AKT phosphorylation and a trend toward an increase in AMPK phosphorylation were observed following social isolation, accompanied by reduced GLUT-4 levels. Social isolation also induced a reduction of phosphorylation of the insulin receptor, of AKT and GLUT-2, and a decreased phosphorylation of AMPK in the liver. Furthermore, a significant reduction in hepatic CPT1 and PPAR-α levels was detected. ISO rats also showed significant elevations in hepatic ROS amount, lipid peroxidation and NOX4 expression, whereas no differences were detected in NOX2 and NOX1 levels. Expression of SOD2 in the mitochondrial fraction and SOD1 in the cytosolic fraction was not altered following social isolation, whereas SOD activity was increased. Furthermore, a decrease of hepatic CAT and GSH amount was observed in ISO rats compared to GRP animals. Our data suggest that the increased oxidant status and antioxidant capacity modifications may trigger hepatic and systemic insulin resistance, by altering signal hormone pathway and sustaining subsequent alteration of glucose homeostasis and metabolic impairment observed in the social isolation model of psychosis.

Palmitoylethanolamide dampens neuroinflammation and anxiety-like behavior in obese mice.

High-fat diet (HFD) consumption leads to obesity and a chronic state of low-grade inflammation, named metainflammation. Notably, metainflammation contributes to neuroinflammation due to the increased levels of circulating free fatty acids and cytokines. It indicates a strict interplay between peripheral and central counterparts in the pathogenic mechanisms of obesity-related mood disorders. In this context, the impairment of internal hypothalamic circuitry runs in tandem with the alteration of other brain areas associated with emotional processing (i.e., hippocampus and amygdala). Palmitoylethanolamide (PEA), an endogenous lipid mediator belonging to the N-acylethanolamines family, has been extensively studied for its pleiotropic effects both at central and peripheral level. Our study aimed to elucidate PEA capability in limiting obesity-induced anxiety-like behavior and neuroinflammation-related features in an experimental model of HFD-fed obese mice. PEA treatment promoted an improvement in anxiety-like behavior of obese mice and the systemic inflammation, reducing serum pro-inflammatory mediators (i.e., TNF-α, IL-1ß, MCP-1, LPS). In the amygdala, PEA increased dopamine turnover, as well as GABA levels. PEA also counteracted the overactivation of HPA axis, reducing the expression of hypothalamic corticotropin-releasing hormone and its type 1 receptor. Moreover, PEA attenuated the immunoreactivity of Iba-1 and GFAP and reduced pro-inflammatory pathways and cytokine production in both the hypothalamus and hippocampus. This finding, together with the reduced transcription of mast cell markers (chymase 1 and tryptase ß2) in the hippocampus, indicated the weakening of immune cell activation underlying the neuroprotective effect of PEA. Obesity-driven neuroinflammation was also associated with the disruption of blood-brain barrier (BBB) in the hippocampus. PEA limited the albumin extravasation and restored tight junction transcription modified by HFD. To gain mechanistic insight, we designed an in vitro model of metabolic injury using human neuroblastoma SH-SY5Y cells insulted by a mix of glucosamine and glucose. Here, PEA directly counteracted inflammation and mitochondrial dysfunction in a PPAR-α-dependent manner since the pharmacological blockade of the receptor reverted its effects. Our results strengthen the therapeutic potential of PEA in obesity-related neuropsychiatric comorbidities, controlling neuroinflammation, BBB disruption, and neurotransmitter imbalance involved in behavioral dysfunctions.

Effect of High-Titer Convalescent Plasma on Progression to Severe Respiratory Failure or Death in Hospitalized Patients With COVID-19 Pneumonia: A Randomized Clinical Trial.

Importance: Convalescent plasma (CP) has been generally unsuccessful in preventing worsening of respiratory failure or death in hospitalized patients with COVID-19 pneumonia. Objective: To evaluate the efficacy of CP plus standard therapy (ST) vs ST alone in preventing worsening respiratory failure or death in patients with COVID-19 pneumonia. Design, Setting, and Participants: This prospective, open-label, randomized clinical trial enrolled (1:1 ratio) hospitalized patients with COVID-19 pneumonia to receive CP plus ST or ST alone between July 15 and December 8, 2020, at 27 clinical sites in Italy. Hospitalized adults with COVID-19 pneumonia and a partial pressure of oxygen-to-fraction of inspired oxygen (Pao2/Fio2) ratio between 350 and 200 mm Hg were eligible. Interventions: Patients in the experimental group received intravenous high-titer CP (≥1:160, by microneutralization test) plus ST. The volume of infused CP was 200 mL given from 1 to a maximum of 3 infusions. Patients in the control group received ST, represented by remdesivir, glucocorticoids, and low-molecular weight heparin, according to the Agenzia Italiana del Farmaco recommendations. Main Outcomes and Measures: The primary outcome was a composite of worsening respiratory failure (Pao2/Fio2 ratio <150 mm Hg) or death within 30 days from randomization. Results: Of the 487 randomized patients (241 to CP plus ST; 246 to ST alone), 312 (64.1%) were men; the median (IQR) age was 64 (54.0-74.0) years. The modified intention-to-treat population included 473 patients. The primary end point occurred in 59 of 231 patients (25.5%) treated with CP and ST and in 67 of 239 patients (28.0%) who received ST (odds ratio, 0.88; 95% CI, 0.59-1.33; P = .54). Adverse events occurred more frequently in the CP group (12 of 241 [5.0%]) compared with the control group (4 of 246 [1.6%]; P = .04). Conclusions and Relevance: In patients with moderate to severe COVID-19 pneumonia, high-titer anti-SARS-CoV-2 CP did not reduce the progression to severe respiratory failure or death within 30 days. Trial Registration: ClinicalTrials.gov Identifier: NCT04716556.

Sex-tailored pharmacology and COVID-19: Next steps towards appropriateness and health equity.

Making gender bias visible allows to fill the gaps in knowledge and understand health records and risks of women and men. The coronavirus disease 2019 (COVID-19) pandemic has shown a clear gender difference in health outcomes. The more severe symptoms and higher mortality in men as compared to women are likely due to sex and age differences in immune responses. Age-associated decline in sex steroid hormone levels may mediate proinflammatory reactions in older adults, thereby increasing their risk of adverse outcomes, whereas sex hormones and/or sex hormone receptor modulators may attenuate the inflammatory response and provide benefit to COVID-19 patients. While multiple pharmacological options including anticoagulants, glucocorticoids, antivirals, anti-inflammatory agents and traditional Chinese medicine preparations have been tested to treat COVID-19 patients with varied levels of evidence in terms of efficacy and safety, information on sex-targeted treatment strategies is currently limited. Women may have more benefit from COVID-19 vaccines than men, despite the occurrence of more frequent adverse effects, and long-term safety data with newly developed vectors are eagerly awaited. The prevalent inclusion of men in randomized clinical trials (RCTs) with subsequent extrapolation of results to women needs to be addressed, as reinforcing sex-neutral claims into COVID-19 research may insidiously lead to increased inequities in health care. The huge worldwide effort with over 3000 ongoing RCTs of pharmacological agents should focus on improving knowledge on sex, gender and age as pillars of individual variation in drug responses and enforce appropriateness.

The Therapeutic Potential of Celastrol in Central Nervous System Disorders: Highlights from In Vitro and In Vivo Approaches.

Celastrol, the most abundant compound derived from the root of Tripterygium wilfordii, largely used in traditional Chinese medicine, has shown preclinical and clinical efficacy for a broad range of disorders, acting via numerous mechanisms, including the induction of the expression of several neuroprotective factors, the inhibition of cellular apoptosis, and the decrease of reactive oxygen species (ROS). Given the crucial implication of these pathways in the pathogenesis of Central Nervous System disorders, both in vitro and in vivo studies have focused their attention on the possible use of this compound in these diseases. However, although most of the available studies have reported significant neuroprotective effects of celastrol in cellular and animal models of these pathological conditions, some of these data could not be replicated. This review aims to discuss current in vitro and in vivo lines of evidence on the therapeutic potential of celastrol in neurodegenerative diseases, including Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and cadmium-induced neurodegeneration, as well as in psychiatric disorders, such as psychosis and depression. In vitro and in vivo studies focused on celastrol effects in cerebral ischemia, ischemic stroke, traumatic brain injury, and epilepsy are also described.

Sublingual AKBA Exerts Antidepressant Effects in the Aß-Treated Mouse Model.

The 3-O-acetyl-11-keto-ß-boswellic acid (AKBA) is the most active compound of Boswellia serrata proposed for treating neurodegenerative disorders, including Alzheimer's disease (AD), characterized in its early phase by alteration in mood. Accordingly, we have previously demonstrated that an intracerebroventricular injection of soluble amyloid beta 1-42 (Aß) peptide evokes a depressive-like phenotype in rats. We tested the protective effects of AKBA in the mouse model of an Aß-induced depressive-like phenotype. We evaluated the depressive-like behavior by using the tail suspension test (TST) and the splash test (ST). Behavioral analyses were accompanied by neurochemical quantifications, such as glutamate (GLU), kynurenine (KYN) and monoamines, and by biochemical measurements, such as glial fibrillary acid protein (GFAP), CD11b and nuclear factor kappa B (NF-kB), in mice prefrontal cortex (PFC) and hippocampus (HIPP). AKBA prevented the depressive-like behaviors induced by Aß administration, since we recorded a reduction in latency to initiate self-care and total time spent to perform self-care in the ST and reduced time of immobility in the TST. Likewise, the increase in GLU and KYN levels in PFC and HIPP induced by the peptide injection were reverted by AKBA administration, as well as the displayed increase in levels of GFAP and NF-kB in both PFC and HIPP, but not in CD11b. Therefore, AKBA might represent a food supplement suitable as an adjuvant for therapy of depression in early-stage AD.

N-3 PUFA Prevent Oxidative Stress in a Rat Model of Beta-Amyloid-Induced Toxicity.

Polyunsaturated fatty acids (PUFA) are involved in brain disorders associated to amyloid beta (Aß) toxicity for which oxidative stress, neurochemical dysfunctions, and neuroinflammation are underlying mechanisms. Here, mechanisms through which lifelong exposure to n-3 PUFA-enriched or n-6/n-3 balanced diets could elicit a protective role in a rat model of Aß-induced toxicity were investigated. To this aim, we quantified hippocampal reactive oxygen species (ROS) amount, 8-hydroxy-2'-deoxyguanosine and interleukin-10 levels, NADPH oxidase (NOX) 1, NOX2, superoxide dismutase 1, and glutathione contents, as well as plasmatic malondialdehyde. Moreover, in the same experimental groups, we assessed tryptophan, serotonin, and its turnover, kynurenine, and noradrenaline amounts. Results showed increased hippocampal ROS and NOX2 levels, serotonin turnover, kynurenine, and noradrenaline contents in Aß-treated rats. Both n-6/n-3 balanced and n-3 PUFA enriched diets reduced ROS production, NOX1 and malondialdehyde levels, serotonin turnover, and kynurenine amount in Aß-injected rats, while increasing NOX2, superoxide dismutase 1, and serotonin contents. No differences in plasmatic coenzyme Q10, reduced glutathione (GSH) and tryptophan levels were detected among different experimental groups, whereas GSH + oxidized glutathione (GSSG) levels were increased in sham animals fed with n-3 PUFA enriched diet and in Aß-treated rats exposed to both n-6/n-3 balanced and n-3 enriched diets. In addition, Aß-induced decrease of interleukin-10 levels was prevented by n-6/n-3 PUFA balanced diet. N-3 PUFA enriched diet further increased interleukin-10 and 8-hydroxy-2'-deoxyguanosine levels. In conclusion, our data highlight the possible neuroprotective role of n-3 PUFA in perturbation of oxidative equilibrium induced by Aß-administration.