Inflammation as common link to progressive neurological diseases.

Life expectancy has increased immensely over the past decades, bringing new challenges to the health systems as advanced age increases the predisposition for many diseases. One of those is the burden of neurologic disorders. While many hypotheses have been placed to explain aging mechanisms, it has been widely accepted that the increasing pro-inflammatory status with advanced age or "inflammaging" is a main determinant of biological aging. Furthermore, inflammaging is at the cornerstone of many age-related diseases and its involvement in neurologic disorders is an exciting hypothesis. Indeed, aging and neurologic disorders development in the elderly seem to share some basic pathways that fundamentally converge on inflammation. Peripheral inflammation significantly influences brain function and contributes to the development of neurological disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Understanding the role of inflammation in the pathogenesis of progressive neurological diseases is of crucial importance for developing effective treatments and interventions that can slow down or prevent disease progression, therefore, decreasing its social and economic burden.

The effects of delta-9-tetrahydrocannabinol administration in the regulation of female rat sociosexual behaviour.

By targeting the endocannabinoid system, delta-9-tetrahydrocannabinol (THC) modulates female motivated behaviours, influenced by sex hormones. Both medial preoptic nucleus (MPN) and ventromedial nucleus of the hypothalamus (VMN) are involved in the modulation of female sexual responses. The first triggers proceptivity, whereas the ventrolateral division of the latter (VMNvl) triggers receptivity. These nuclei are modulated by glutamate, which inhibits female receptivity, and GABA, which has a dichotomous action in female sexual motivation. Here, we evaluated the action of THC on the modulation of social and sexual behaviours, on signalling pathways of MPN and VMNvl and how sex hormones influence these parameters. Young ovariectomized female rats, given sex hormones (oestradiol benzoate, EB, and progesterone, P) and THC were used for behavioural testing and for immunofluorescence analyses of vesicular glutamate transporter 2 (VGlut2) and GAD (glutamic acid decarboxylase)67 expression. Results showed that females given EB + P exhibited a higher preference for male partner, as well as higher proceptivity and a higher receptivity than control or females given only EB. Females treated with THC presented similar responses in control or EB + P female rats and even more facilitated behavioural responses in EB females than the ones that did not receive THC. Immunofluorescence results in the MPN exhibited a decreased expression of GAD67 and VGlut2 in EB + THC-treated female rats. Within VMNvl of EB-primed rats no changes in the expression of both proteins were observed after THC exposure. This study demonstrates how the possible outcomes of endocannabinoid system instability within hypothalamic neuron connectivity can modify female rat sociosexual behaviour.

A Semi-Automatic Method for the Quantification of Astrocyte Number and Branching in Bulk Immunohistochemistry Images.

Immunohistochemical staining of cell and molecular targets in brain samples is a powerful tool that can provide valuable information on neurological mechanisms. However, post-processing of photomicrographs acquired after 3,3'-Diaminobenzidine (DAB) staining is particularly challenging due to the complexity associated with the size, samples number, analyzed targets, image quality, and even the subjectivity inherent to the analysis by different users. Conventionally, this analysis relies on the manual quantification of distinct parameters (e.g., the number and size of cells and the number and length of cell branching) in a large set of images. These represent extremely time-consuming and complex tasks, defaulting the processing of high amounts of information. Here we describe an improved semi-automatic method to quantify glial fibrillary acidic protein (GFAP)-labelled astrocytes in immunohistochemistry images of rat brains, at magnifications as low as 20×. This method is a straightforward adaptation of the Young & Morrison method, using ImageJ's plugin Skeletonize, coupled with intuitive data processing in datasheet-based software. It allows swifter and more efficient post-processing of brain tissue samples, regarding astrocyte size and number quantification, the total area occupied, as well as astrocyte branching and branch length (indicators of astrocyte activation), thus contributing to better understand the possible inflammatory response developed by astrocytes.

A Clinically Relevant Dosage of Mitoxantrone Disrupts the Glutathione and Lipid Metabolic Pathways of the CD-1 Mice Brain: A Metabolomics Study.

Long-term cognitive dysfunction, or "chemobrain", has been observed in cancer patients treated with chemotherapy. Mitoxantrone (MTX) is a topoisomerase II inhibitor that binds and intercalates with DNA, being used in the treatment of several cancers and multiple sclerosis. Although MTX can induce chemobrain, its neurotoxic mechanisms are poorly studied. This work aimed to identify the adverse outcome pathways (AOPs) activated in the brain upon the use of a clinically relevant cumulative dose of MTX. Three-month-old male CD-1 mice were given a biweekly intraperitoneal administration of MTX over the course of three weeks until reaching a total cumulative dose of 6 mg/kg. Controls were given sterile saline in the same schedule. Two weeks after the last administration, the mice were euthanized and their brains removed. The left brain hemisphere was used for targeted profiling of the metabolism of glutathione and the right hemisphere for an untargeted metabolomics approach. The obtained results revealed that MTX treatment reduced the availability of cysteine (Cys), cysteinylglycine (CysGly), and reduced glutathione (GSH) suggesting that MTX disrupts glutathione metabolism. The untargeted approach revealed metabolic circuits of phosphatidylethanolamine, catecholamines, unsaturated fatty acids biosynthesis, and glycerolipids as relevant players in AOPs of MTX in our in vivo model. As far as we know, our study was the first to perform such a broad profiling study on pathways that could put patients given MTX at risk of cognitive deficits.

Panic-like responses of female Wistar rats confronted by Bothrops alternatus pit vipers, or exposure to acute hypoxia: Effect of oestrous cycle.

Anxiety-related diseases are more than twice as common in women than in men, and in women, symptoms may be exacerbated during the late luteal phase of the menstrual cycle. Despite this, most research into the underlying mechanisms, which drives drug development, have been carried out using male animals. In an effort to redress this imbalance, we compared responses of male and female Wistar rats during exposure to two unconditioned threatening stimuli that evoke panic-related defensive behaviours: confrontation with a predator (Bothrops alternatus) and acute exposure to hypoxia (7% O2 ). Threatened by venomous snake, male and female rats initially displayed defensive attention, risk assessment, and cautious interaction with the snake, progressing to defensive immobility to overt escape. Both males and females displayed higher levels of risk assessment but less interaction with the predator. They also spent more time in the burrow, displaying inhibitory avoidance, and more time engaged in defensive attention, and non-oriented escape behaviour. In females, anxiety-like behaviour was most pronounced in the oestrous and proestrus phases whereas panic-like behaviour was more pronounced during the dioestrus phase, particularly during late dioestrus. Acute hypoxia evoked panic-like behaviour (undirected jumping) in both sexes, but in females, responsiveness in late dioestrus was significantly greater than at other stages of the cycle. The results reveal that females respond in a qualitatively similar manner to males during exposure to naturally occurring threatening stimuli, but the responses of females is oestrous cycle dependent with a significant exacerbation of panic-like behaviour in the late dioestrus phase.

Early unhealthy eating habits underlie morpho-functional changes in the liver and adipose tissue in male rats.

Early-life consumption of high-fat and sugar-rich foods is recognized as a major contributor for the onset of metabolic dysfunction and its related disorders, including diabetes and nonalcoholic fatty liver disease. The lifelong impact of early unhealthy eating habits that start at younger ages remains unclear. Therefore, to better understand the effects of diet, it is essential to evaluate the structural and functional changes induced in metabolic organs and potential mechanisms underlying those changes. To investigate the long-term effects of eating habits, young male rats were exposed to high-sugar and high-energy diets. After 14 weeks, body composition was assessed, and histopathological changes were analyzed in the liver and adipose tissue. Serum biochemical parameters were also determined. Expression of inflammatory markers in the liver was evaluated by immunohistochemistry. Our results revealed that serum levels of glucose, creatinine, aspartate transaminase (AST), alanine transaminase (ALT), and lipid profile were increased in rats red high-sugar and high-energy diets. Histopathological alterations were observed, including abnormal hepatocyte organization and lipid droplet accumulation in the liver, and abnormal structure of adipocytes. In both unhealthy diet groups, hepatic expression of Toll-like receptor 4 (TLR4), cyclooxygenase 2 (COX-2), and E-selectin were increased, as well as a biomarker of oxidative stress. Together, our data demonstrated that unhealthy diets induced functional and structural changes in the metabolic organs, suggesting that proinflammatory and oxidative stress mechanisms trigger the hepatic alterations and metabolic dysfunction.

Four decades of chemotherapy-induced cognitive dysfunction: comprehensive review of clinical, animal and in vitro studies, and insights of key initiating events.

Cognitive dysfunction has been one of the most reported and studied adverse effects of cancer treatment, but, for many years, it was overlooked by the medical community. Nevertheless, the medical and scientific communities have now recognized that the cognitive deficits caused by chemotherapy have a strong impact on the morbidity of cancer treated patients. In fact, chemotherapy-induced cognitive dysfunction or 'chemobrain'  (also named also chemofog) is at present a well-recognized effect of chemotherapy that could affect up to 78% of treated patients. Nonetheless, its underlying neurotoxic mechanism is still not fully elucidated. Therefore, this work aimed to provide a comprehensive review using PubMed as a database to assess the studies published on the field and, therefore, highlight the clinical manifestations of chemobrain and the putative neurotoxicity mechanisms.In the last two decades, a great number of papers was published on the topic, mainly with clinical observations. Chemotherapy-treated patients showed that the cognitive domains most often impaired were verbal memory, psychomotor function, visual memory, visuospatial and verbal learning, memory function and attention. Chemotherapy alters the brain's metabolism, white and grey matter and functional connectivity of brain areas. Several mechanisms have been proposed to cause chemobrain but increase of proinflammatory cytokines with oxidative stress seem more relevant, not excluding the action on neurotransmission and cellular death or impaired hippocampal neurogenesis. The interplay between these mechanisms and susceptible factors makes the clinical management of chemobrain even more difficult. New studies, mainly referring to the underlying mechanisms of chemobrain and protective measures, are important in the future, as it is expected that chemobrain will have more clinical impact in the coming years, since the number of cancer survivors is steadily increasing.

Chemobrain: mitoxantrone-induced oxidative stress, apoptotic and autophagic neuronal death in adult CD-1 mice.

Mitoxantrone (MTX) is a topoisomerase II inhibitor used to treat a wide range of tumors and multiple sclerosis but associated with potential neurotoxic effects mediated by hitherto poorly understood mechanisms. In adult male CD-1 mice, the underlying neurotoxic pathways of a clinically relevant cumulative dose of 6 mg/kg MTX was evaluated after biweekly administration for 3 weeks and sacrifice 1 week after the last administration was undertaken. Oxidative stress, neuronal damage, apoptosis, and autophagy were analyzed in whole brain, while coronal brain sections were used for a closer look in the hippocampal formation (HF) and the prefrontal cortex (PFC), as these areas have been signaled out as the most affected in 'chemobrain'. In the whole brain, MTX-induced redox imbalance shown as increased endothelial nitric oxide synthase and reduced manganese superoxide dismutase expression, as well as a tendency to a decrease in glutathione levels. MTX also caused diminished ATP synthase ß expression, increased autophagic protein LC3 II and tended to decrease p62 expression. Postsynaptic density protein 95 expression decreased in the whole brain, while hyperphosphorylation of Tau was seen in PFC. A reduction in volume was observed in the dentate gyrus (DG) and CA1 region of the HF, while GFAP-ir astrocytes increased in all regions of the HF except in the DG. Apoptotic marker Bax increased in the PFC and in the CA3 region, whereas p53 decreased in all brain areas evaluated. MTX causes damage in the brain of adult CD-1 mice in a clinically relevant cumulative dose in areas involved in memory and cognition.

Unhealthy Diets Induce Distinct and Regional Effects on Intestinal Inflammatory Signalling Pathways and Long-Lasting Metabolic Dysfunction in Rats.

The intestinal epithelium is a principal site for environmental agents' detection. Several inflammation- and stress-related signalling pathways have been identified as key players in these processes. However, it is still unclear how the chronic intake of inadequate nutrients triggers inflammatory signalling pathways in different intestinal regions. We aimed to evaluate the impact of unhealthy dietary patterns, starting at a younger age, and the association with metabolic dysfunction, intestinal inflammatory response, and obesity in adulthood. A rat model was used to evaluate the effects of the consumption of sugary beverages (HSD) and a Western diet (WD), composed of ultra-processed foods. Both diets showed a positive correlation with adiposity index, but a positive correlation was found between the HSD diet and the levels of blood glucose and triglycerides, whereas the WD diet correlated positively with triglyceride levels. Moreover, a distinct inflammatory response was associated with either the WD or HSD diets. The WD induced an increase in TLR2, TLR4, and nuclear factor-kappa B (NF-κB) intestinal gene expression, with higher levels in the colon and overexpression of the inducible nitric oxide synthase. In turn, the HSD diet induced activation of the TLR2-mediated NF-κB signalling pathway in the small intestine. Altogether, these findings support the concept that early intake of unhealthy foods and nutrients are a main exogenous signal for disturbances of intestinal immune mechanisms and in a region-specific manner, ultimately leading to obesity-related disorders in later life.

Effects of ovariectomy on inputs from the medial preoptic area to the ventromedial nucleus of the hypothalamus of young adult rats.

Puberty is an important phase of development when the neural circuit organization is transformed by sexual hormones, inducing sexual dimorphism in adult behavioural responses. The principal brain area responsible for the control of the receptive component of female sexual behaviour is the ventrolateral division of the ventromedial nucleus of the hypothalamus (VMHvl), which is known for its dependency on ovarian hormones. Inputs to the VMHvl originating from the medial preoptic nucleus (MPN) are responsible for conveying essential information that will trigger such behaviour. Here, we investigated the pattern of the projection of the MPN to the VMHvl in rats ovariectomized at the onset of puberty. Sprague Dawley rats were ovariectomized (OVX) at puberty and then subjected to iontophoretic injections of the neuronal anterograde tracer Phaseolus vulgaris leucoagglutinin into the MPN once they reached 90 days of age. This study analysed the connectivity pattern established between the MPN and the VMH that is involved in the neuronal circuit responsible for female sexual behaviour in control and OVX rats. The data show the changes in the organization of the connections observed in the OVX adult rats that displayed a reduced axonal length for the MPN fibres reaching the VMHvl, suggesting that peripubertal ovarian hormones are relevant to the organization of MPN connections with structures involved in the promotion of female sexual behaviour.

Behavioral and brain morphological analysis of non-inflammatory and inflammatory rat models of preterm brain injury.

Investigations using preclinical models of preterm birth have much contributed, together with human neuropathological studies, for advances in our understanding of preterm brain injury. Here, we evaluated whether the neurodevelopmental and behavioral consequences of preterm birth induced by a non-inflammatory model of preterm birth using mifepristone would differ from those after inflammatory prenatal transient hypoxia-ischemia (TSHI) model. Pregnant Wistar rats were either injected with mifepristone, and pups were delivered on embryonic day 21 (ED21 group), or laparotomized on the 18th day of gestation for 60 min of uterine arteries occlusion. Rat pups were tested postnatally for characterization of developmental milestones and, after weaning, they were behaviorally tested for anxiety and for spatial learning and memory. One month later, brains were processed for quantification of doublecortin (DCX)- and neuropeptide Y (NPY)-immunoreactive cells, and cholinergic varicosities in the hippocampus. ED21 rats did not differ from controls with respect to neonatal developmental milestones, anxiety, learning and memory functions, and neurochemical parameters. Conversely, in TSHI rats the development of neonatal reflexes was delayed, the levels of anxiety were reduced, and spatial learning and memory was impaired; in the hippocampus, the total number of DCX and NPY cells was increased, and the density of cholinergic varicosities was reduced. With these results we suggest that a preterm birth, in a non-inflammatory prenatal environment, does not significantly change neonatal development and adult neurologic outcome. On other hand, prenatal hypoxia and ischemia (inflammation) modifies developmental trajectory, learning and memory, neurogenesis, and NPY GABAergic and cholinergic brain systems.

Uterine histopathological changes induced by acute administration of tamoxifen and its modulation by sex steroid hormones.

The endometrium is a particular sensitive target tissue for estradiol that is able to promptly modify its structure. Tamoxifen (TAM), a selective estrogen receptor modulator, was shown to promote a spectrum of uterine abnormalities, though the morphological and stereological effects of this drug in uterus is not clear. In this way, we have used an established model of ovariectomy followed by estradiol benzoate (EB) or TAM treatment and analyzed their effects in uterine histopathology and proliferation. Administration of EB promotes the unfolding and proliferation of the endometrium stroma, increasing uterine volume. No changes were found in uterine histomorphometric analysis upon TAM administration, except in the thickness of the luminal epithelium and endometrium layer. The latter may result from increased complexity and glandular volume density also observed in TAM treatment. In addition, EB induced PAX2 expression, an oncogene commonly found in epithelial tumors of the female genital tract, an effect that was weakened by previous TAM administration. Although treatments did not affect stroma cells proliferating index, in epithelial cells and, contrary to TAM, EB increased PCNA and not Ki67 expression. Collectively, our data suggest that the acute administration of TAM induces ERα-dependent atrophy of the uterine tissue and decreased the expression of proliferating cellular markers. On the contrary, if administered prior to EB, TAM is able to attenuate the action of the hormone in uterine morphology and biochemistry.

Hepatic effects of long-term tamoxifen administration to cycling female rats.

The metabolic implications of tamoxifen (TAM) used as preventive therapy of young premenopausal women with high risk of breast cancer is unknown. To unravel this problem, an animal model of long-term TAM administration to cycling young adult female rats was used to evaluate its effects in the liver. Body weight and food consumption were monitored, and at the end of the study, both parameters were lower in TAM-treated rats. Biochemical measurements showed that the TAM administration induced alterations in serum levels of liver enzymes when compared with control rats at different stages of the estrous cycle. In TAM-treated rats, lower glycogen storage was observed in hepatocytes close to the portal areas and pericentrolobular cells had a higher concentration of glycogen. Liver sections of TAM-treated rats presented mild steatosis-a high percentage of area occupied by lipid droplets in the hepatocytes. These results point to metabolic changes upon long-term TAM therapy.

Effects of tamoxifen on neuronal morphology, connectivity and biochemistry of hypothalamic ventromedial neurons: Impact on the modulators of sexual behavior.

Tamoxifen (TAM) is a selective estrogen receptor modulator, widely used in the treatment and prevention of estrogen-dependent breast cancer. Although with great clinical results, women on TAM therapy still report several side effects, such as sexual dysfunction, which impairs quality of life. The anatomo-functional substrates of the human sexual behavior are still unknown; however, these same substrates are very well characterized in the rodent female sexual behavior, which has advantage of being a very simple reflexive response, dependent on the activation of estrogen receptors (ERs) in the ventrolateral division of the hypothalamic ventromedial nucleus (VMNvl). In fact, in the female rodent, the sexual behavior is triggered by increasing circulation levels of estradiol that changes the nucleus neurochemistry and modulates its intricate neuronal network. Therefore, we considered of notice the examination of the possible neurochemical alterations and the synaptic plasticity impairment in VMNvl neurons of estradiol-primed female rats treated with TAM that may be in the basis of this neurological disorder. Accordingly, we used stereological and biochemical methods to study the action of TAM in axospinous and axodendritic synaptic plasticity and on ER expression. The administration of TAM changed the VMNvl neurochemistry by reducing ERα mRNA and increasing ERß mRNA expression. Furthermore, present results show that TAM induced neuronal atrophy and reduced synaptic connectivity, favoring electrical inactivity. These data suggest that these cellular and molecular changes may be a possible neuronal mechanism of TAM action in the disruption of the VMNvl network, leading to the development of behavioral disorders.

Heavy Alcohol Consumption Effects on Blood Pressure and on Kidney Structure Persist After Long-Term Withdrawal.

BACKGROUND/AIMS: Heavy ethanol consumption is a risk factor for hypertension and prompts organ damage. There is no information regarding the impact of long-term heavy ethanol consumption on kidney structure and function linking to their hypertensive effects nor the repercussions after withdrawal. METHODS: Rats were exposed to ethanol for 24 weeks and, afterwards, a group was assigned to withdrawal for 8 weeks. Blood pressure (BP) was measured and serum biochemical parameters were quantified. Glomerular volume density, areal density of glomerular tuft and renal corpuscles were determined. Angiotensin II type 1 receptor (AT1R) protein expression was evaluated. RESULTS: Twenty-four weeks of ethanol consumption causes atrophy of renal corpuscles and glomeruli and reduces the volume of glomeruli. Glomerular changes induced by ethanol consumption were still evident after withdrawal. Renal AT1R levels were increased in ethanol-treated rats and returned to control levels during withdrawal. Ethanol consumption also induced an increase in BP, uric acid and albumin levels. Upon withdrawal, systolic and mean arterial pressures decreased, but were still higher than in controls rats. CONCLUSION: Ethanol consumption induces changes in glomerular morphology associated with increased BP and AT1R expression. Long-term withdrawal was inefficient to restore the structural integrity of renal corpuscles and in lowering systolic pressure.

The Role of Formulations in the Ageing Process of Vinyl Acetate Based Emulsion Films: A Multivariate Approach.

Vinyl acetate (VAc)-based emulsions represent one of the main media used by modern and contemporary artists. Their long-term behaviour is still not completely understood, especially due to the scarce knowledge on the influence of other compounds in the formulation, which may impact ageing over time. Besides the polymer backbone based on vinyl acetate, other co-monomers and additives can be added to the emulsion to alter the final film's physical, chemical, and optical properties. By extension, the formulation will also impact the long-term stability of artworks and objects on which it has been applied, as well as possible current and future conservation interventions such as cleaning. For those reasons, studies shedding light on the correlation between composition and long-term stability are largely necessary. In this study, different emulsions, including homopolymers, copolymers, plasticised, and un-plasticised compositions, were gathered and artificially aged. A multivariate analyses approach based on the application of principal component analyses (PCA) and hierarchical cluster analyses (HCA) was employed for the first time on the combination of data obtained by pH, contact angle (CA), colour measurements, Fourier transform infrared spectroscopy in attenuated total reflection (FTIR-ATR), and size exclusion chromatography (SEC). This approach helped to highlight the changes that occurred during ageing and find correlations with the formulation compositions. The results further sustain the thesis that not all vinyl acetate-based emulsions are chemically the same and that their formulation deeply impacts their long-term behaviour.

Pharmaceutical-mediated neuroimmune modulation in psychiatric/psychological adverse events.

The therapeutic use of many pharmaceuticals, including small molecules and biological therapies, has been associated with the onset of psychiatric and psychological adverse events (PPAEs), posing substantial concerns to patients' health and safety. These events, which encompass mood (e.g., depression, schizophrenia, suicidal ideation) and cognitive changes (e.g., learning and memory impairment, dementia) often remain undetected until advanced stages of clinical trials or pharmacovigilance, mostly because the mechanisms underlying the onset of PPAEs remain poorly understood. In recent years, the role of neuroimmune modulation (comprising an intricate interplay between various cell types and signaling pathways) in PPAEs has garnered substantial interest. Indeed, understanding these complex interactions would substantially contribute to increase the ability to predict the potential onset of PPAEs during preclinical stages of a new drug's R&D. This review provides a comprehensive summary of the most recent advances in neuroimmune modulation-related mechanisms contributing to the onset of PPAEs and their association with specific pharmaceuticals. Reported data strongly support an association between neuroimmune modulation and the onset of PPAEs. Pharmaceuticals may target specific molecular pathways and pathway elements (e.g., cholinergic and serotonergic systems), which in turn may directly or indirectly impact the inflammatory status and the homeostasis of the brain, regulating inflammation and neuronal function. Also, modulation of the peripheral immune system by pharmaceuticals that do not permeate the blood-brain barrier (e.g., monoclonal antibodies) may alter the neuroimmunomodulatory status of the brain, leading to PPAEs. In summary, this review underscores the diverse pathways through which drugs can influence brain inflammation, shedding light on potential targeted interventions.

Unraveling the Hippocampal Molecular and Cellular Alterations behind Tramadol and Tapentadol Neurobehavioral Toxicity.

Tramadol and tapentadol are chemically related opioids prescribed for the analgesia of moderate to severe pain. Although safer than classical opioids, they are associated with neurotoxicity and behavioral dysfunction, which arise as a concern, considering their central action and growing misuse and abuse. The hippocampal formation is known to participate in memory and learning processes and has been documented to contribute to opioid dependence. Accordingly, the present study assessed molecular and cellular alterations in the hippocampal formation of Wistar rats intraperitoneally administered with 50 mg/kg tramadol or tapentadol for eight alternate days. Alterations were found in serum hydrogen peroxide, cysteine, homocysteine, and dopamine concentrations upon exposure to one or both opioids, as well as in hippocampal 8-hydroxydeoxyguanosine and gene expression levels of a panel of neurotoxicity, neuroinflammation, and neuromodulation biomarkers, assessed through quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical analysis of hippocampal formation sections showed increased glial fibrillary acidic protein (GFAP) and decreased cluster of differentiation 11b (CD11b) protein expression, suggesting opioid-induced astrogliosis and microgliosis. Collectively, the results emphasize the hippocampal neuromodulator effects of tramadol and tapentadol, with potential behavioral implications, underlining the need to prescribe and use both opioids cautiously.

Doxorubicin-induced neurotoxicity differently affects the hippocampal formation subregions in adult mice.

Doxorubicin (DOX) is an anthracycline used to treat a wide range of tumours. Despite its effectiveness, it is associated with a long range of adverse effects, of which cognitive deficits stand out. The present study aimed to assess the neurologic adverse outcome pathways of two clinically relevant cumulative doses of DOX. Adult male CD-1 mice received biweekly intraperitoneal administrations for 3 weeks until reaching cumulative doses of 9 mg/kg (DOX9) or 18 mg/kg (DOX18). Animals were euthanized one week after the last administration, and biomarkers of oxidative stress and brain metabolism were evaluated in the whole brain. Coronal sections of fixed brains were used for specific determinations of the prefrontal cortex (PFC) and hippocampal formation (HF). In the whole brain, DOX18 tended to disrupt the antioxidant defences, affecting glutathione levels and manganese superoxide dismutase expression. Considering the regional analysis, DOX18 increased the volume of all brain areas evaluated, while GFAP-immunoreactive astrocytes decreased in the dentate gyrus (DG) and increased in the CA3 region of HF, both in a dose-dependent manner. Concerning the apoptosis pathway, whereas Bax increased in the DOX9 group, it decreased in the DOX18 group. Only in the latter group did Bcl-2 levels also decrease. While p53 only increased in the CA3 region of the DOX9 group, AIF increased in the PFC and DG of DOX18. Finally, phosphorylation of Tau decreased with the highest DOX dose in DG and CA3, while TNF-α levels increased in CA1 of DOX18. Our results indicate new pathways not yet described that could be responsible for the cognitive impairments observed in treated patients.

Structural, functional and behavioral impact of allergic rhinitis on olfactory pathway and prefrontal cortex.

BACKGROUND: Allergic rhinitis (AR) has been identified as a cause of olfactory dysfunction. Beyond the classic symptoms, AR has been associated with altered sleep patterns, a decline in cognitive performance and higher likelihood of depression and anxiety. The olfactory pathway has been postulated to be a possible link between nasal inflammation and central nervous system (CNS) modifications. Thus, we aimed to investigate the structural, functional and behavioral changes in the olfactory pathway and related areas in an animal model of AR. METHODS: AR was induced in adult Wistar rats by ovalbumin sensitization and challenge. Following olfactory and behavioral tests we investigated the synaptic structure of the olfactory bulb (OB), anterior olfactory nuclei (AON), piriform cortex and prefrontal cortex (PFC), by immunofluorescence detection of synaptophysin (Syn) and glutamatergic, GABAergic and dopaminergic neuronal markers. RESULTS: We detected a significant decrease in Syn in the glomerular layer (GL) of OB and in the PFC of the AR group. Additionally, the optical density of GAD67 and VGLUT2 was reduced in the OB, AON and PFC, compared to controls. The behavioral tests demonstrated olfactory dysfunction and reduced male aggressiveness in AR rats, but we did not find any difference in the cognition and anxiety-like behavior. CONCLUSIONS: We confirmed olfactory dysfunction in a rat model of AR and we identified modifications in synaptic activity by reduction of Syn optical density in the GL of the OB and in the PFC. This was accompanied by structural changes in glutamatergic and GABAergic activity in essential components of the olfactory pathway and PFC.