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.

Effects of deficiency or supplementation of riboflavin on energy metabolism: a systematic review with preclinical studies.

CONTEXT: Riboflavin (vitamin B2) is a water-soluble micronutrient considered to be a precursor of the nucleotides flavin adenine dinucleotide and flavin mononucleotide. This vitamin makes up mitochondrial complexes and participates as an enzymatic cofactor in several mechanisms associated with energy metabolism. OBJECTIVE: This systematic review collected and discussed the most relevant results on the role of riboflavin in the energy metabolism of lipids, proteins, and carbohydrates. DATA SOURCES: A systematic search was carried out in the PubMed-Medline, Scopus, Embase, and Web of Science databases using the PICOS (Population, Intervention, Comparison, Outcome, Study design) strategy. DATA EXTRACTION: The screening of studies went through 2 stages following predefined eligibility criteria. The information extracted covered reference details, study design, population characteristics, experimental model, treatment parameters and dosage, route of administration, duration of treatment, and results found. DATA ANALYSIS: The risk of bias was assessed using the SYRCLE Risk of Bias (RoB) tool for in vivo studies and the QUIN tool adapted for in vitro studies, utilizing 10 domains, including selection bias, performance bias, detection bias, attrition bias, reporting bias, and other biases, to evaluate the methodological quality of the included studies. CONCLUSION: This review concludes that riboflavin regulates energy metabolism by activating primary metabolic pathways and is involved in energy balance homeostasis.

Influence of maternal high-fat diet on offspring's locomotor activity during anxiety-related behavioral tests: A systematic review.

The aim of this review was to summarize and discuss the impact of a maternal high-fat diet on the locomotor activity of offspring during anxiety-related behavioral tests. A search was performed in the LILACS, Web of Science, SCOPUS and PUMBED databases, using the following inclusion criteria: studies in which rodent dams were submitted to a high-fat diet during gestation and/or lactation and in which the locomotor activity parameters of offspring were evaluated during an anxiety-related test. Twenty-three articles met these criteria and were included. Most studies, 14 out of 23, found that a maternal high-fat diet did not alter offspring locomotor activity. Six articles found that a maternal high-fat diet increased the locomotor activity of offspring, while three found decreased locomotion. This effect may be associated with the initial response to the test and the fact that it was the first day of exposure to the apparatus.

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.

Effects of riboflavin in the treatment of brain damage caused by oxygen deprivation: an integrative systematic review.

Brain oxygen deprivation causes morphological damage involved in the formation of serious pathological conditions such as stroke and cerebral palsy. Therapeutic methods for post-hypoxia/anoxia injuries are limited and still have deficiencies in terms of safety and efficacy. Recently, clinical studies of stroke have reported the use of drugs containing riboflavin for post-injury clinical rehabilitation, however, the effects of vitamin B2 on exposure to cerebral oxygen deprivation are not completely elucidated. This review aimed to investigate the potential antioxidant, anti-inflammatory and neuroprotective effects of riboflavin in cerebral hypoxia/anoxia. After a systematic search, 21 articles were selected, 8 preclinical and 12 clinical studies, and 1 translational study. Most preclinical studies used B2 alone in models of hypoxia in rodents, with doses of 1-20 mg/kg (in vivo) and 0.5-5 µM (in vitro). Together, these works suggested greater regulation of lipid peroxidation and apoptosis and an increase in neurotrophins, locomotion, and cognition after treatment. In contrast, several human studies have administered riboflavin (5 mg) in combination with other Krebs cycle metabolites, except one study, which used only B2 (20 mg). A reduction in lactic acidosis and recovery of sensorimotor functions was observed in children after treatment with B2, while adults and the elderly showed a reduction in infarct volume and cognitive rehabilitation. Based on findings from preclinical and clinical studies, we conclude that the use of riboflavin alone or in combination acts beneficially in correcting the underlying brain damage caused by hypoxia/anoxia and its inflammatory, oxidative, and behavioral impairments.

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.

Neonatal treatment with resveratrol decreases postural and strength impairments and improves mitochondrial function in the somatosensory cortex rats submitted to cerebral palsy.

Cerebral palsy is a neurodevelopmental disease characterized by postural, motor, and cognitive disorders, being one of the main causes of physical and intellectual disability in childhood. To minimize functional impairments, the use of resveratrol as a therapeutic strategy is highlighted due to its neuroprotective and antioxidant effects in different regions of the brain. Thus, this study aimed to investigate the effects of neonatal treatment with resveratrol on postural development, motor function, oxidative balance, and mitochondrial biogenesis in the brain of rats submitted to a cerebral palsy model. Neonatal treatment with resveratrol attenuated deficits in somatic growth, postural development, and muscle strength in rats submitted to cerebral palsy. Related to oxidative balance, resveratrol in cerebral palsy decreased the levels of MDA and carbonyls. Related to mitochondrial biogenesis, was observed in animals with cerebral palsy treated with resveratrol, an increase in mRNA levels of TFAM, in association with the increase of citrate synthase activity. The data demonstrated a promising effect of neonatal resveratrol treatment, improving postural and muscle deficits induced by cerebral palsy. These findings were associated with improvements in oxidative balance and mitochondrial biogenesis in the brain of rats submitted to cerebral palsy.

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.

Effectiveness of Polyphenols on Perinatal Brain Damage: A Systematic Review of Preclinical Studies.

Polyphenol supplementation during early life has been associated with a reduction of oxidative stress and neuroinflammation in diseases caused by oxygen deprivation, including cerebral palsy, hydrocephaly, blindness, and deafness. Evidence has shown that perinatal polyphenols supplementation may alleviate brain injury in embryonic, fetal, neonatal, and offspring subjects, highlighting its role in modulating adaptative responses involving phenotypical plasticity. Therefore, it is reasonable to infer that the administration of polyphenols during the early life period may be considered a potential intervention to modulate the inflammatory and oxidative stress that cause impairments in locomotion, cognitive, and behavioral functions throughout life. The beneficial effects of polyphenols are linked with several mechanisms, including epigenetic alterations, involving the AMP-activated protein kinase (AMPK), nuclear factor kappa B (NF-κB), and phosphoinositide 3-kinase (PI3K) pathways. To highlight these new perspectives, the objective of this systematic review was to summarize the understanding emerging from preclinical studies about polyphenol supplementation, its capacity to minimize brain injury caused by hypoxia-ischemia in terms of morphological, inflammatory, and oxidative parameters and its repercussions for motor and behavioral functions.

Therapeutic advances for treating memory impairments in perinatal brain injuries with implications for cerebral palsy: a systematic review and meta-analysis of preclinical studies.

Cerebral palsy (CP) is a neurodevelopmental disorder caused by damage to the immature brain. CP is considered the main cause of physical disability in childhood. Studies have shown that memory function and emotional behaviour are significantly impaired in CP. Current thought is that interventions for neuromotor damaged play a prominent role, but neglects the memory acquisition problems that affect the functioning and quality of life of these children. This systematic review aims to map and analyse pre-clinical interventions used to treat memory formation problems resulting from CP. For this, a search was carried out in the Pubmed, Web of Science, Scopus and Lilacs databases. Then, eligibility, extraction date and evaluation of the methodological quality of the studies were determined. 52 studies were included in this review, and 27 were included in a meta-analysis. Assessing memory performance as a primary outcome, and structural and biochemical changes in the hippocampus as a secondary outcome. CP models were reported to be induced by hypoxia-ischemia, oxygen deprivation and liposaccharide (LPS) exposure, resulting in impairments in the formation of short-term and long-term memory in adult life. A reduction in escape latency and dwell time were observed in the target quadrant as well as an increase in the time needed for the rodents to find the platform in the Morris Water Maze (MWM). Brain injuries during the perinatal period are considered an insult that negatively impacts hippocampus maturation and causes impairment in memory formation in adult life. Some studies reported that regions of the hippocampus such as the dentate gyrus and cornu ammonis 1 were impaired in CP, noting an increase in oxidative stress enzymes and pro-inflammatory cytokines, associated with a reduction in BDNF and neurogenesis levels. These were reported to cause a reduction in the number of neurons and the volume of the hippocampus, in addition to an increase in astrogliosis and apoptosis of neurons and difficulties in forming new memories similar to those that occur in children with CP. Interventions that reduced neuroinflammation and the presence of free radicals were highlighted as a therapy for the memory disturbance present in CP. Preclinical studies registered treatments with oxygen interventions, resveratrol and erythropoietin, which were able to reduce the damage to the hippocampus and promote improvements in memory and behaviour. In the meta-analysis of selected studies, we observed favorable results, through effect size, for the use of oxygen interventions (SDM -6.83 95% CI [-7.91, -5.75], Z = 12.38, p = 0.03; I2 = 71%), erythropoietin (SDM -3.16 95% CI [-4.27, -2.05], Z = 5.58, p = 0.002; I2 = 82%) and resveratrol (SDM -2.42 95% CI [-3.19, - 1.66], Z = 6.21, p = 0.01; I2 = 77%), stimulating plastic responses in the hippocampus and facilitating the memory formation, with these presenting positive effects in general (SDM -2.84 95% CI [-3.10, -2.59], Z = 22.00; p < 0.00001; I2 = 92.9%). These studies demonstrate possible avenues of intervention for memory alterations in experimental models of early brain injuries, highlighting promising interventions that can facilitate the maturation of the hippocampus and memory formation and, consequently, minimize functional problems that arise during development.

Neonatal treatment with fluoxetine alters locomotor activity and the cortical glial/neuron index in rats with cerebral palsy.

Cerebral palsy (CP) is characterized by motor disorders, including deficits in locomotor activity, coordination, and balance. Selective serotonin reuptake inhibitors have been shown to play an important role in brain plasticity. This study investigates the effect of neonatal treatment using fluoxetine on locomotor activity and histomorphometric parameters of the primary somatosensory cortex (S1) in rats submitted to an experimental model of CP. CP was found to reduce bodyweight and locomotion parameters and also to increase the glia/neuron index in the S1. Administration of fluoxetine 10 mg/kg reduced bodyweight, impaired locomotor activity parameters, and increased the number of glial cells and the glia/neuron ratio in the S1 in rats with CP. However, treatment with fluoxetine 5 mg/kg was not found to be associated with adverse effects on locomotor activity and seems to improve histomorphometric parameters by way of minor changes in the S1 in animals with CP. These results thus indicate that experimental CP, in combination with the use of a high dose of fluoxetine (10 mg/kg), impairs locomotor and histomorphometric parameters in the S1, while treatment with a low dose of fluoxetine (5 mg/kg) averts the negative outcomes associated with a high dose of fluoxetine in relation to these parameters but produces no protective effect.

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.

Neonatal kaempferol exposure attenuates gait and strength deficits and prevents altered muscle phenotype in a rat model of cerebral palsy.

Cerebral palsy (CP) is characterized by brain damage at a critical period of development of the central nervous system, and, as a result, motor, behavioural and learning deficits are observed in those affected. Flavonoids such as kaempferol have demonstrated potential anti-inflammatory and neuroprotective properties for neurological disorders. This study aimed to assess the effects of neonatal treatment with kaempferol on the body development, grip strength, gait performance and morphological and biochemical phenotype of skeletal muscle in rats subjected to a model of CP. The groups were formed by randomly allocating male Wistar rats after birth to four groups as follows: C = control treated with vehicle, K = control treated with kaempferol, CP = CP treated with vehicle and CPK = CP treated with kaempferol. The model of CP involved perinatal anoxia and sensorimotor restriction of the hind paws during infancy, from the second to the 28th day of postnatal life. Treatment with kaempferol (1 mg/kg) was performed intraperitoneally during the neonatal period. Body weight and length, muscle strength, gait kinetics and temporal and spatial parameters were evaluated in the offspring. On the 36th day of postnatal life, the animals were euthanized for soleus muscle dissection. The muscle fibre phenotype was assessed using the myofibrillar ATPase technique, and the muscle protein expression was measured using the Western blot technique. A reduction in the impact of CP on body phenotype was observed, and this also attenuated deficits in muscle strength and gait. Treatment also mitigated the impact on muscle phenotype by preventing a reduction in the proportion of oxidative fibres and in the histomorphometric parameters in the soleus muscle of rats in the CP group. The results demonstrate that neonatal treatment with kaempferol attenuated gait deficits and impaired muscle strength and muscle maturation in rats subjected to a model of CP.

Creatine supplementation to improve the peripheral and central inflammatory profile in cerebral palsy.

This opinion paper presents a brief review on the potential use of Creatine (Cr) to improve the inflammatory profile in individuals with Cerebral Palsy (CP). CP is a condition that causes muscle atrophy followed by reduced strength and altered muscle tone. The prevalence of chronic diseases is higher in people with CP due to this, which are often associated with peripheral inflammation, but there are no studies that have evaluated central inflammation in this condition. Nevertheless, the anti-inflammatory action of Cr has already been observed in different types of studies. Thus, the use of experimental models of CP to evaluate the expression of the inflammatory markers, especially in the brain, as well as approaches to reduce the impairments already observed becomes essential. Results obtained in these preclinical studies may contribute to the quality of therapeutic strategies offered to children suffering from CP, the most common cause of chronic motor disability in childhood.

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.

The role of vitamin B12 in viral infections: a comprehensive review of its relationship with the muscle-gut-brain axis and implications for SARS-CoV-2 infection.

This comprehensive review establishes the role of vitamin B12 as adjunct therapy for viral infections in the treatment and persistent symptoms of COVID-19, focusing on symptoms related to the muscle-gut-brain axis. Vitamin B12 can help balance immune responses to better fight viral infections. Furthermore, data from randomized clinical trials and meta-analysis indicate that vitamin B12 in the forms of methylcobalamin and cyanocobalamin may increase serum vitamin B12 levels, and resulted in decreased serum methylmalonic acid and homocysteine concentrations, and decreased pain intensity, memory loss, and impaired concentration. Among studies, there is much variation in vitamin B12 doses, chemical forms, supplementation time, and administration routes. Larger randomized clinical trials of vitamin B12 supplementation and analysis of markers such as total vitamin B12, holotranscobalamin, total homocysteine and methylmalonic acid, total folic acid, and, if possible, polymorphisms and methylation of genes need to be conducted with people with and without COVID-19 or who have had COVID-19 to facilitate the proper vitamin B12 form to be administered in individual treatment.

Effects of flavonols on emotional behavior and compounds of the serotonergic system: A preclinical systematic review.

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that regulates multiple psychophysiological functions. An imbalance of 5-HT in the brain can modulate emotional behavior such as depression and anxiety. Substances, such as flavonols, naturally found in some plants and foods have beneficial effects on psychiatric disorders, have been studied. The aim of this systematic review was to investigate the effects of flavonols on morphological, physiological, and cellular aspects of the serotonergic system as well as on some behaviors modulated by this system. Literature searches were performed in the LILACS, Web of Science, Scopus, PubMed and Sigle via Open Grey databases, from which 1725 studies were found. Using a predefined protocol registered on the CAMARADES website, 18 studies were chosen for qualitative synthesis. Internal validity was assessed using the SYRCLE's risk of bias tool. The Kappa index was also measured to analyze agreement among the reviewers. The results of this systematic review showed that flavonols have been reported to modify physiological aspects of the serotonergic system, increasing levels of serotonin and decreasing levels of its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) and promoting antioxidant effects in encephalic regions. Moreover, the results showed that flavonols can also modulate of the serotonergic system, being associated with antidepressant and anxiolytic activities. Additionally, flavonols were found to not have psychostimulant effect; they can, however, reverse damage to locomotor activity.

Locomotion is impacted differently according to the perinatal brain injury model: Meta-analysis of preclinical studies with implications for cerebral palsy.

BACKGROUND: Different approaches to reproduce cerebral palsy (CP) in animals, contribute to the knowledge of the pathophysiological mechanism of this disease and provide a basis for the development of intervention strategies. Locomotion and coordination are the main cause of disability in CP, however, few studies highlight the quantitative differences of CP models, on locomotion parameters, considering the methodologies to cause brain lesions in the perinatal period. METHODS: Studies with cerebral palsy animal models that assess locomotion parameters were systematically retrieved from Medline/PubMed, SCOPUS, LILACS, and Web of Science. Methodological evaluation of included studies and quantitative assessment of locomotion parameters were performed after eligibility screening. RESULTS: CP models were induced by hypoxia-ischemia (HI), Prenatal ischemia (PI), lipopolysaccharide inflammation (LPS), intraventricular haemorrhage (IVH), anoxia (A), sensorimotor restriction (SR), and a combination of different models. Overall, 63 studies included in qualitative synthesis showed a moderate quality of evidence. 16 studies were included in the quantitative meta-analysis. Significant reduction was observed in models that combined LPS with HI related to distance traveled (SMD -7.24 95 % CI [-8.98, -5.51], Z = 1.18, p < 0.00001) and LPS with HI or anoxia with sensory-motor restriction (SMD -6.01, 95 % CI [-7.67, -4.35], Z = 7.11), or IVH (SMD -4.91, 95 % CI [-5.84, -3.98], Z = 10.31, p < 0.00001) related to motor coordination. CONCLUSION: The combination of different approaches to reproduce CP in animals causes greater deficits in locomotion and motor coordination from the early stages of life to adulthood. These findings contribute to methodological refinement, reduction, and replacement in animal experimentation, favoring translational purposes.