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.

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.

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.