Creatine supplementation increases postnatal growth and strength and prevents overexpression of pro-inflammatory interleukin 6 in the hippocampus in an experimental model of cerebral palsy.

ABSTRACTObjectives: The aim of this study was thus to evaluate the effect of Cr supplementation on morphological changes and expression of pro-inflammatory cytokines in the hippocampus and on developmental parameters. Methods: Male Wistar rat pups were submitted to an experimental model of CP. Cr was administered via gavage from the 21st to the 28th postnatal day, and in water after the 28th, until the end of the experiment. Body weight (BW), food consumption (FC), muscle strength, and locomotion were evaluated. Expression of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α) were assessed in the hippocampus by quantitative real-time polymerase chain reaction. Iba1 immunoreactivity was assessed by immunocytochemistry in the hippocampal hilus. Results: Experimental CP caused increased density and activation of microglial cells, and overexpression of IL-6. The rats with CP also presented abnormal BW development and impairment of strength and locomotion. Cr supplementation was able to reverse the overexpression of IL-6 in the hippocampus and mitigate the impairments observed in BW, strength, and locomotion. Discussion: Future studies should evaluate other neurobiological characteristics, including changes in neural precursor cells and other cytokines, both pro- and anti-inflammatory.

Neonatal kaempferol exposure attenuates impact of cerebral palsy model on neuromotor development, cell proliferation, microglia activation, and antioxidant enzyme expression in the hippocampus of rats.

OBJECTIVES: This study aims to assess the effect of neonatal treatment with kaempferol on neuromotor development, proliferation of neural precursor cells, the microglia profile, and antioxidant enzyme gene expression in the hippocampus. METHODS: A rat model of cerebral palsy was established using perinatal anoxia and sensorimotor restriction of hindlimbs during infancy. Kaempferol (1 mg/ kg) was intraperitoneally administered during the neonatal period. RESULTS: Neonatal treatment with kaempferol reduces the impact of the cerebral palsy model on reflex ontogeny and on the maturation of physical features. Impairment of locomotor activity development and motor coordination was found to be attenuated by kaempferol treatment during the neonatal period in rats exposed to cerebral palsy. Neonatal treatment of kaempferol in cerebral palsy rats prevents a substantial reduction in the number of neural precursor cells in the dentate gyrus of the hippocampus, an activated microglia profile, and increased proliferation of microglia in the sub-granular zone and in the granular cell layer. Neonatal treatment with kaempferol increases gene expression of superoxide dismutase and catalase in the hippocampus of rats submitted to the cerebral palsy model. DISCUSSION: Kaempferol attenuates the impact of cerebral palsy on neuromotor behavior development, preventing altered hippocampal microglia activation and mitigating impaired cell proliferation in a neurogenic niche in these rats. Neonatal treatment with kaempferol also increases antioxidant defense gene expression in the hippocampus of rats submitted to the cerebral palsy model.

Dietary flavonoid kaempferol reduces obesity-associated hypothalamic microglia activation and promotes body weight loss in mice with obesity.

BACKGROUND: Obesity results from an unbalance in the ingested and burned calories. Energy balance (EB) is critically regulated by the hypothalamic arcuate nucleus (ARC) by promoting appetite or anorectic actions. Hypothalamic inflammation, driven by high activation of the microglia, has been reported as a key mechanism involved in the development of diet-induced obesity. Kaempferol (KF), a flavonoid-type polyphenol present in a large number of fruits and vegetables, was shown to regulate both energy metabolism and inflammation. OBJECTIVES: In this work, we studied the effects of both the central and peripheral treatment with KF on hypothalamic inflammation and EB regulation in mice with obesity. METHODS: Obese adult mice were chronically (40 days) treated with KF (0.5 mg/kg/day, intraperitoneally). During the treatment, body weight, food intake (FI), feed efficiency (FE), glucose tolerance, and insulin sensitivity were determined. Analysis of microglia activation in the ARC of the hypothalamus at the end of the treatment was also performed. Body weight, FI, and FE changes were also evaluated in response to 5µg KF, centrally administrated. RESULTS: Chronic administration of KF decreased ∼43% of the density, and ∼30% of the ratio, of activated microglia in the arcuate nucleus. These changes were accompanied by body weight loss, decreased FE, reduced fasting blood glucose, and a tendency to improve insulin sensitivity. Finally, acute central administration of KF reproduced the effects on EB triggered by peripheral administration. CONCLUSION: These findings suggest that KF might fight obesity by regulating central processes related to EB regulation and hypothalamic inflammation.

Polyphenols and Neurodegenerative Diseases: Potential Effects and Mechanisms of Neuroprotection.

The increase in people's longevity has, consequently, led to more brain involvement and neurodegenerative diseases, which can become complicated and lead to chronic degenerative diseases, thereby presenting greater public health problems. Medicinal plants have been used since ancient times and contain high concentrations of molecules, including polyphenols. It has been proven that polyphenols, which are present in various natural sources can provide curative effects against various diseases and brain disorders through neuroprotective effects. These neuroprotective effects are mainly attributed to their ability to cross the blood-brain barrier, eliminate reactive oxygen species, and cause the chelation of metal ions. Polyphenols increase the concentration of neurotrophic factors and bind directly to the membrane receptors of these neurotrophic factors, to modulate and activate the signaling cascades that allow the plasticity, survival, proliferation, and growth of neuronal cells, thereby allowing for better learning, memory, and cognition. Moreover, polyphenols have no serious adverse side effects resulting from their consumption.

The 5-HT1A receptor agonist, 8-OH-DPAT, attenuates long-lasting pain in imiquimod-induced psoriasis in mice.

Psoriasis pain is a common symptom underestimated and rarely evaluated in psoriasis clinical trials. This work aimed to investigate whether the development of secondary chronic allodynia and hyperalgesia in the imiquimod (IMQ)-induced psoriasis mice model could be modulated by anti-inflammatory agents and compound 48/80 (C48/80) and to determine whether the activation of 5-HT1A receptor modulates these nociceptive behaviours. C57BL/6 male mice were treated with 5% IMQ for 7 days. The paw withdrawal responses to von Frey filaments (10 and 250 mN) were used to assess the allodynia and hyperalgesia. Nociceptive behaviours were also evaluated using ketorolac 15 mg/kg s.c., adalimumab 10 mg/kg s.c. and C48/80 10 mg/kg i.p. Then, the serum serotonin and the impact of 8-OH-DPAT (1 mg/kg s.c), a 5-HT1A receptor agonist, on long-lasting pain were examined. Mice receiving IMQ showed enhanced nociception, which decreased with all tested compounds. The serum serotonin in the IMQ group showed a significant decrease (947.042 ng/ml) regarding the control group (1143.68 ng/ml). The pretreatment with 8-OH-DPAT alleviated pain-related behaviours. These results suggest that the long-lasting pain resulting from psoriasis inflammation is also associated with the serotonergic system. The 5-HT1A receptor should be further explored as a potential therapeutic target for psoriasis pain modulation.

Effects of the Treatment with Flavonoids on Metabolic Syndrome Components in Humans: A Systematic Review Focusing on Mechanisms of Action.

Diets high in bioactive compounds, such as polyphenols, have been used to mitigate metabolic syndrome (MetS). Polyphenols are a large group of naturally occurring bioactive compounds, classified into two main classes: non-flavonoids and flavonoids. Flavonoids are distributed in foods, such as fruits, vegetables, tea, red wine, and cocoa. Studies have already demonstrated the benefits of flavonoids on the cardiovascular and nervous systems, as well as cancer cells. The present review summarizes the results of clinical studies that evaluated the effects of flavonoids on the components of the MetS and associated complications when offered as supplements over the long term. The results show that flavonoids can significantly modulate several metabolic parameters, such as lipid profile, blood pressure, and blood glucose. Only theaflavin and catechin were unable to affect metabolic parameters. Moreover, only body weight and body mass index were unaltered. Thus, the evidence presented in this systematic review offers bases in support of a flavonoid supplementation, held for at least 3 weeks, as a strategy to improve several metabolic parameters and, consequently, reduce the risk of diseases associated with MetS. This fact becomes stronger due to the rare side effects reported with flavonoids.

Prenatal immobilization stress and postnatal maternal separation cause differential neuroendocrine responses to fasting stress in adult male rats.

Prenatal immobilization stress (PNS) and postnatal maternal separation (MS180) are two widely used rodent models of early-life stress (ELS) that affect the hypothalamus-pituitary-adrenal (HPA) axis, cause behavioral alterations, and affect glucose tolerance in adults. We compared anxiety-like behavior, coping strategies, and HPA axis activity in PNS and MS180 adult (4-month-old) male rats and assessed their glucose tolerance and HPA axis response after mild fasting stress. Both PNS and MS180 induced a passive coping strategy in the forced swimming test, without affecting anxiety-like behavior in the elevated plus-maze. Moreover, both PNS and MS180 increased the hypothalamic corticotropin-releasing hormone expression; however, only MS180 increased the circulating corticosterone levels. Both early life stressors increased fasting glucose levels and this effect was significantly higher in PNS rats. MS180 rats showed impaired glucose tolerance 120 min after intravenous glucose administration, whereas PNS rats displayed an efficient homeostatic response. Moreover, MS180 rats showed higher circulating corticosteroid levels in response to fasting stress (overnight fasting, 12 hr), which were restored after glucose administration. In conclusion, early exposure to postnatal MS180, unlike PNS, increases the HPA axis response to moderate fasting stress, indicating a differential perception of fasting as a stressor in these two ELS models.

Early Life Stress Activates Glial Cells in the Hippocampus but Attenuates Cytokine Secretion in Response to an Immune Challenge in Rat Pups.

OBJECTIVE: Early life stress (ELS) increases the vulnerability to developing psychopathological disorders in adulthood that are accompanied by brain inflammatory processes. However, it is not known how a combined double hit (stress and immune) at an early age affects the response of the neuroimmune system. Here we investigated the effect of periodic maternal separation (MS) followed by administration of lipopolysaccharide (LPS) on glial cells in the CA3 region and hilus of the hippocampus and on cytokine release on postnatal day (PN) 15. METHODS: Male rat pups were subjected to MS (3 h/day, PN1-14). MS and control pups received a single LPS injection (1 mg/kg of body weight) on PN14. They were subjected to an open field test 1 h later. The pups were sacrificed 90 min after LPS injection (PN14) or on PN15 for cytokine or immunohistological analyses, respectively. RESULTS: LPS reduced the locomotion and induced high corticosterone levels in treated pups. MS or LPS reduced microglial density and activated microglial cells in the hippocampal CA3 and hilus regions. Microglial activation was highest in MS-LPS pups. The astrocyte density was mildly reduced by MS or LPS in the CA3 region and hilus, but the reduction was maximal in MS-LPS pups. LPS increased the secretion of plasmatic interleukin (IL)-1ß, tumor necrosis factor-α, and IL-6, and of hippocampal IL-1ß protein, but these were attenuated in MS-LPS pups. CONCLUSION: Although MS and LPS activate neuroimmune cells, stress attenuates the hippocampal and peripheral cytokine response to LPS through an as-yet unidentified adaptive mechanism. These results provide information regarding the neurobiology of stress and inflammation.

Maternal separation activates microglial cells and induces an inflammatory response in the hippocampus of male rat pups, independently of hypothalamic and peripheral cytokine levels.

Adult animals subjected to chronic stress show an inflammatory response in the hippocampus which has been related to cognitive dysfunction and psychopathology. However the immediate consequences of early life stress on hippocampal glial cells have not been studied. Here we analyzed the effects of maternal separation (MS) on astrocyte and microglial cell morphology in the hippocampal hilus, compared the expression of cytokines in the hippocampus and hypothalamus, and the peripheral response of cytokines, on postnatal day (PD) 15. Male rat pups of MS (3h/day, PD1-PD14) and Control (CONT) pups showed similar microglial cell densities in the hilus, but MS pups presented more activated microglia. MS decreased astrocyte density and the number of processes in the hilus. Cytokine mRNA expression (qPCR) was analyzed in MS and CONT groups, sacrificed (i) under basal (B) conditions or (ii) after a single stress event (SS) at PN15. In hippocampal extracts, MS increased IL-1ß mRNA, under B and SS conditions while IL-6 and TNF-α did not change. In hypothalamic tissue, MS increased TNF-α and IL-6 mRNA, but not IL-1b, after SS. Peripheral concentrations of IL-1ß were decreased under B and SS conditions in MS; IL-6 concentration increased after SS in MS pups, and TNF-α concentration was unchanged. In conclusion, MS activates microglial cells and decreases astrocyte density in the hippocampus. A differential cytokine expression is observed in the hippocampus and the hypothalamus after MS, and after SS. Also, MS triggers an independent response of peripheral cytokines. These specific responses together could contribute to decrease hippocampal neurogenesis and alter the neuroendocrine axis.

Early Life Stress Influences Oxidative Stress Enzyme Activities in Liver, Heart, Kidney, Suprarenal Glands, and Pancreas in Male and Female Rat Pups.

Early life stress (ELS) is a risk factor for the development of chronic diseases resulting from functional alterations of organs in the cardiorespiratory and renal systems. This work studied the changes in oxidative stress enzyme activities (EAs) of SOD, CAT, GPX, GR, GST, NOS, MDA, and FRAP in different organs (heart, liver, kidney, adrenal glands (AGs), and pancreas) of male and female Sprague-Dawley rat pups on postnatal day (PN) 15, immediately after basal and acute or chronic stress conditions were accomplished, as follows: basal control (BC; undisturbed maternal pups care), stress control (SC; 3 h maternal separation on PN15), basal maternal separation (BMS; daily 3 h maternal separation on PN 1-14), and stress maternal separation (SMS; daily 3 h maternal separation on PN 1-14 and 3 h maternal separation on PN15). Acute or long-term stress resulted in overall oxidative stress, increase in EA, and reduced antioxidant capacity in these organs. Some different response patterns, due to precedent SMS, were observed in specific organs, especially in the AGs. Acute stress exposure increases the EA, but chronic stress generates a response in the antioxidant system in some of the organs studied and is damped in response to a further challenge.

Integrative Approach of Treating Early Undernutrition with an Enriched Black Corn Chip, Study on a Murine Model.

Undernutrition (UN) increases child vulnerability to illness and mortality. Caused by a low amount and/or poor quality of food intake, it impacts physical, cognitive, and social development. Modern types of food consumption have given highly processed food a higher cultural value compared to minimally processed food. OBJECTIVE: The objective of this study was to evaluate the effect on growth, metabolism, physical activity (PA), memory, inflammation, and toxicity of an enriched black corn chip (BC) made with endemic ingredients on post-weaned UN mice. METHODS: A chip was made with a mixture of black corn, fava beans, amaranth, and nopal cactus. To probe the effects of UN, UN was induced in 3wo post-weaned male C57Bl/6j mice through a low-protein diet (LPD-50% of the regular requirement of protein) for 3w. Then, the BC was introduced to the animals' diet (17%) for 5w; murinometric parameters were measured, as were postprandial glucose response, PA, and short-term memory. Histological analysis was conducted on the liver and kidneys to measure toxicity. Gene expression related to energy balance, thermogenesis, and inflammation was measured in adipose and hypothalamic tissues. RESULTS: Treatment with the BC significantly improved mouse growth, even with a low protein intake, as evidenced by a significant increase in body weight, tail length, cerebral growth, memory improvement, physical activation, normalized energy expenditure (thermogenesis), and orexigenic peptides (AGRP and NPY). It decreased anorexigenic peptides (POMC), and there was no tissue toxicity. CONCLUSIONS: BC treatment, even with persistent low protein intake, is a promising strategy against UN, as it showed efficacy in correcting growth deficiency, cognitive impairment, and metabolic problems linked to treatment by adjusting energy expenditure, which led to the promotion of energy intake and regulation of thermogenesis, all by using low-cost, accessible, and endemic ingredients.

Neonatal resveratrol treatment in cerebral palsy model recovers neurodevelopment impairments by restoring the skeletal muscle morphology and decreases microglial activation in the cerebellum.

Cerebral Palsy (CP) is the main motor disorder in childhood resulting from damage to the developing brain. Treatment perspectives are required to reverse the primary damage caused by the early insult and consequently to recover motor skills. Resveratrol has been shown to act as neuroprotection with benefits to skeletal muscle. This study aimed to investigate the effects of neonatal resveratrol treatment on neurodevelopment, skeletal muscle morphology, and cerebellar damage in CP model. Wistar rat pups were allocated to four experimental groups (n = 15/group) according CP model and treatment: Control+Saline (CS), Control+Resveratrol (CR), CP + Saline (CPS), and CP + Resveratrol (CPR). CP model associated anoxia and sensorimotor restriction. CP group showed delay in the disappearance of the palmar grasp reflex (p < 0.0001) and delay in the appearance of reflexes of negative geotaxis (p = 0.01), and free-fall righting (p < 0.0001), reduced locomotor activity and motor coordination (p < 0.05) than CS group. These motor skills impairments were associated with a reduction in muscle weight (p < 0.001) and area and perimeter of soleus end extensor digitorum longus muscle fibers (p < 0.0001), changes in muscle fibers typing pattern (p < 0.05), and the cerebellum showed signs of neuroinflammation due to elevated density and percentage of activated microglia in the CPS group compared to CS group (p < 0.05). CP animals treated with resveratrol showed anticipation of the appearance of negative geotaxis and free-fall righting reflexes (p < 0.01), increased locomotor activity (p < 0.05), recovery muscle fiber types pattern (p < 0.05), and reversal of the increase in density and the percentage of activated microglia in the cerebellum (p < 0.01). Thus, we conclude that neonatal treatment with resveratrol can contribute to the recovery of the delay neurodevelopment resulting from experimental CP due to its action in restoring the skeletal muscle morphology and reducing neuroinflammation from cerebellum.

Neonatal high-dose riboflavin treatment channels energy expenditure towards sensorimotor and somatic development and reduces rodent growth and weight gain by modulating NRF-1 in the hypothalamus.

Metabolic adaptations early in life can drive energy expenditure towards brain and physical development, with less emphasis on body mass gain and somatic growth. Dietary or pharmacological manipulations can influence these processes, but to date, the effects provided by riboflavin have not been studied. The study aimed to evaluate the effects of neonatal treatment with different doses of riboflavin on sensorimotor and somatic development in rodents. Based on this, the following experimental groups were formed: Control (C, 0 mg/kg), Riboflavin 1 (R1, 1 mg/kg), Riboflavin 2 (R2, 10 mg/kg) and Riboflavin 3 (R3, 100 mg/kg). Treatment with 100 mg/kg riboflavin anticipated the reflex ontogeny of righting, cliff aversion, negative geotaxis, and free-fall righting. Intervention with 10 and 100 mg/kg of riboflavin anticipated the reflex maturation of vibrissae placement. Eye-opening, upper incisor eruption, and lower incisor eruption reached maturational age more quickly for animals treated with 100 mg/kg, while caudal growth and body weight gain were reduced from the second week of treatment, for groups R2 and R3. Pearson's correlation analysis indicated a positive association between the administration of high doses of riboflavin and murine growth in the first week of treatment. There was, however, a negative association between treatment with a high dose of riboflavin and growth in the second week of administration, coinciding with a reduction in body weight gain in the R3 group. Treatment with 100 mg/kg of riboflavin also reduced energy expenditure parameters in the open field and catwalk. Although high-dose treatment stimulates the physiological plasticity of the CNS and reduces weight gain, hepatic parameters were preserved, highlighting the participation of the liver in the supply of fatty acids for neural maturation. Furthermore, hypothalamic NRF-1 expression was increased in the R3 group inversely to the reduction in weight gain. Our results suggest that high-dose riboflavin stimulates sensorimotor and somatic development and reduces the energy invested in growth, body weight gain, and locomotor activity, possibly involving NRF-1 gene modulation in the hypothalamus.

Prolactin administration during early postnatal life decreases hippocampal and olfactory bulb neurogenesis and results in depressive-like behavior in adulthood.

Tight regulation of hormone and neurochemical milieu during developmental periods is critical for adequate physiological functions. For instance, activation of peptide systems during early life stress induces morphological changes in the brain resulting in depression and anxiety disorders. Prolactin (PRL) exerts different actions within the brain; it regulates neurogenesis and modulates neuroendocrine functions in the adult. However, PRL effects during early postnatal life are hardly known. Therefore, we examined whether neonatal administration of PRL influences cell survival in the hippocampal dentate gyrus (DG) and in the olfactory bulb (OB) and whether such influence results in behavioral consequences in adulthood. PRL-treated rat pups (13 mg/kg; PND1 to PND14), injected with BrdU at postnatal day 5 (PND5), showed a decrease in the density of DG BrdU/DCX and BrdU/NeuN-positive cells that survive at PND15. Similarly, PRL treatment decreased the density of BrdU+ cells in the OB compared with VEH. Fluorojade B analysis showed no significant changes in the amount of cell death in the DG between the groups. Postnatal PRL administration induced a passive coping strategy in the forced swimming test in male and female adult rats when compared with control and vehicle groups. Corticosterone endogenous levels at PND12 were not affected by PRL or VEH treatment. Altogether, these results suggest that opposed to its effects in the adult, postnatal PRL treatment affects neurogenesis and results in psychopathology later in life. High PRL levels, as observed in neonates under several pathological states, might contribute to detrimental effects on the developing brain.

Motor deficits are associated with increased glial cell activation in the hypothalamus and cerebellum of young rats subjected to cerebral palsy.

Cerebral palsy (CP) is a syndrome characterized by a wide range of sensory and motor damage, associated with behavioral and cognitive deficits. The aim of the present study was to investigate the potential of a model of CP using a combination of perinatal anoxia and sensorimotor restriction of hind paws to replicate motor, behavioral and neural deficits. A total of 30 of male Wistar rats were divided into Control (C, n = 15), and CP (CP, n = 15) groups. The potential of the CP model was assessed by evaluating food intake, the behavioral satiety sequence, performance on the CatWalk and parallel bars, muscle strength, and locomotor activity. The weight of the encephalon, soleus, and extensor digitorum longus (EDL) muscles, and the activation of glial cells (microglia and astrocytes) were also measured. The CP animals showed delayed satiety, impaired locomotion on the CatWalk and open field test, reduced muscle strength, and reduced motor coordination. CP also reduced the weight of the soleus and muscles, brain weight, liver weight, and quantity of fat in various parts of the body. There was also found to be an increase in astrocyte and microglia activation in the cerebellum and hypothalamus (arcuate nucleus, ARC) of animals subjected to CP.

Resveratrol Reduces Neuroinflammation and Hippocampal Microglia Activation and Protects Against Impairment of Memory and Anxiety-Like Behavior in Experimental Cerebral Palsy.

Cerebral palsy (CP) is a neurodevelopmental disorder characterized by motor and postural impairments. However, early brain injury can promote deleterious effects on the hippocampus, impairing memory. This study aims to investigate the effects of resveratrol treatment on memory, anxiety-like behavior, and neuroinflammation markers in rats with CP. Male Wistar rats were subjected to perinatal anoxia (P0-P1) and sensory-motor restriction (P2-P28). They were treated with resveratrol (10 mg/kg, 0.1 ml/100 g) or saline from P3-P21, being divided into four experimental groups: CS (n = 15), CR (n = 15), CPS (n = 15), and CPR (n = 15). They were evaluated in the tests of novel object recognition (NORT), T-Maze, Light-Dark Box (LDB), and Elevated Plus Maze (EPM). Compared to the CS group, the CPS group has demonstrated a reduced discrimination index on the NORT (p < 0.0001) and alternation on the T-Maze (p < 0.01). In addition, the CPS group showed an increase in permanence time on the dark side in LDB (p < 0.0001) and on the close arms of the EPM (p < 0.001). The CPR group demonstrated an increase in the object discrimination index (p < 0.001), on the alternation (p < 0.001), on the permanence time on the light side (p < 0.0001), and on the open arms (p < 0.001). The CPR group showed a reduction in gene expression of IL-6 (p = 0.0175) and TNF-α (p = 0.0007) and an increase in Creb-1 levels (p = 0.0020). The CPS group showed an increase in the activated microglia and a reduction in cell proliferation in the hippocampus, while CPR animals showed a reduction of activated microglia and an increase in cell proliferation. These results demonstrate promising effects of resveratrol in cerebral palsy behavior impairment through reduced neuroinflammation in the hippocampus.

Melatonin Decreases Circulating Levels of Galectin-3 and Cytokines, Motor Activity, and Anxiety Following Acute Global Cerebral Ischemia in Male Rats.

BACKGROUND: Global cerebral ischemia (GCI) elicits damages to cerebral structures, learning dysfunction, memory impairments, hyperactivity, and anxiety. Circulating levels of galectin-3 (Gal-3) are associated with patient severity and outcome. AIM: To report circulating levels of Gal-3, and cytokines (TNF-α, IL-6, IL-10) in the initial hours (acute) following GCI in a four-vessel occlusion (4-VO) rat model and the effect of melatonin treatment. METHODS: 4-VO model was used to produce GCI using male Sprague-Dawley rats. Groups were: Sham-Veh, Sham-Mel, Isch-Veh and Isch-Mel. Melatonin was administered 30 min after carotid clamp removal. Gal-3 and cytokines levels were measured at 0, 30 min, 6 h and 24 h after the end of cerebral flow interruption using ELISA kits. Motor activity and anxiety were measured using open-field test. RESULTS: Acute GCI (AGCI) followed by reperfusion decreased serum concentrations of TNF-α and increased IL-6 levels 24 h after ischemia, whereas melatonin reduced significantly the concentrations of these cytokines. In all groups IL-10 was higher 30 min and negligible at other times. Circulating levels of Gal-3 were reduced 30 min after ischemia/reperfusion. In the Isch-Mel group the neuroprotective effect generated a reduction in circulating Gal-3 at 6 and 24 h after AGCI, compared with all the groups. Motor activity was increased due to ischemic reperfusion, but acute melatonin treatment reduced locomotion, similar to the control group. Anxiety was reduced in the melatonin group. CONCLUSIONS: Melatonin treatment following AGCI reduces pro-inflammatory factors, Gal-3, motility, and anxiety, therefore it should be considered as supplementary treatment following ischemic stroke.

Long-term activation of hippocampal glial cells and altered emotional behavior in male and female adult rats after different neonatal stressors.

Early life stress increases the risk of developing psychiatric diseases in adulthood. Severe neonatal infections can also contribute to the development of affective illnesses. Stress and infections both trigger the immediate activation of the neuroimmune system. We compared the long-term effects of neonatal single or combined stress-immune challenges on emotional behavior and glial cell responses in the hippocampus. Male and female Sprague Dawley rats were randomly allocated across four conditions: (1) control + vehicle; (2) maternal separation (MS, 3 h/day on postnatal days [PN] 1-14) + vehicle; (3) control + lipopolysaccharide (LPS, 0.5. mg/kg, PN14); (4) MS + LPS. The rats' behaviors were analyzed from PN120 in males and from PN150 in diestrous females. LPS, but not MS, increased anxiety-like behavior in male rats; however, in females, it increased with both challenges. Depressive-like behavior increased after MS-but not LPS-in males and females. Combined stressors increased depressive-like behavior in both sexes. All stressors promoted microglial activation in CA3 and hilus in males and females. MS and LPS increased the astrocytic density within the male hilus, but LPS only increased it in CA3. MS prevented the rise in astrocytic density with LPS. In females, MS reduced the astrocytic population of the hilus and CA3 areas. Taken together, the behavioral and glial cell responses to early life challenges are sex-dependent and cell-type specific. This suggests a sexual dimorphism in the nature of the adverse event faced. These results have implications for understanding the emergence of psychiatric illnesses.

A systematic review of neurogenesis in animal models of early brain damage: Implications for cerebral palsy.

Brain damage during early life is the main factor in the development of cerebral palsy (CP), which is one of the leading neurodevelopmental disorders in childhood. Few studies, however, have focused on the mechanisms of cell proliferation, migration, and differentiation in the brain of individuals with CP. We thus conducted a systematic review of preclinical evidence of structural neurogenesis in early brain damage and the underlying mechanisms involved in the pathogenesis of CP. Studies were obtained from Embase, Pubmed, Scopus, and Web of Science. After screening 2329 studies, 29 studies, covering a total of 751 animals, were included. Prenatal models based on oxygen deprivation, inflammatory response and infection, postnatal models based on oxygen deprivation or hypoxic-ischemia, and intraventricular hemorrhage models showed varying neurogenesis responses according to the nature of the brain damage, the time period during which the brain injury occurred, proliferative capacity, pattern of migration, and differentiation profile in neurogenic niches. Results mainly from rodent studies suggest that prenatal brain damage impacts neurogenesis and curbs generation of neural stem cells, while postnatal models show increased proliferation of neural precursor cells, improper migration, and reduced survival of new neurons.

Prolactin prevents chronic stress-induced decrease of adult hippocampal neurogenesis and promotes neuronal fate.

Chronic exposure to stress results in a reduction of hippocampal neurogenesis and of hippocampal volume. We examined whether prolactin (PRL), a regulator of the stress response and stimulator of neurogenesis in the subventricular zone, influences neurogenesis in the hippocampal dentate gyrus (DG) of chronically stressed adult C57BL/6 male mice. Chronically stressed (4 h daily immobilization for 21 d) or nonstressed mice were treated with either ovine PRL or vehicle between days 1-14. BrdU was injected daily between days 1-7 to evaluate cell survival and fate, or twice on day 21 to evaluate cell proliferation. Hippocampal cell proliferation was unchanged by either stress exposure or PRL at the end of the treatments. In contrast, the number of cells in the DG that incorporated BrdU during the first phase of the experiment and survived to the end of the experiment was decreased in vehicle-treated stressed mice compared with PRL- or vehicle-treated nonstressed control mice. Stressed animals receiving PRL had significantly more BrdU-labeled cells than vehicle-treated stressed mice at this time point. Cell fate analysis revealed a higher percentage of neurons in PRL- compared with vehicle-treated stressed mice. The results demonstrate that PRL protects neurogenesis in the DG of chronically stressed mice and promotes neuronal fate.