Brain injuries during early development can result in a permanent childhood movement and posture disorder known as cerebral palsy (CP). It affects children around the world differently varying depending on access to obstetric and neonatal care in the sociodemographic region (Graham et al., 2019; Gulati and Sondhi, 2017; Maenner et al., 2016; Oskoui et al., 2013; McIntyre et al., 2022). The Global prevalence of CP is estimated at approximately 1.6 per 1000 live births in high-income countries and its prevalence is markedly higher in low- and middle-income countries reaching up to 3.4 per 1000 live births (McIntyre et al., 2022). High-income countries deal with prematurity and morbidities related to low birth weight, while low- and middle-income countries tend to deal with infections in the pre- or post-natal period and perinatal asphyxia (Gulati and Sondhi, 2017; Wimalasundera and Stevenson, 2016).

The early insult that leads to CP occurs during the critical period of development, in other words, the insult occurs at some stage of the window of vulnerability of the central nervous system (CNS) (Marret et al., 2013; Semple et al., 2013). For example, acute or subacute perinatal events such as birth asphyxia are determinants in the white and gray matter lesions generally observed in children with CP (Marret et al., 2013). A window of greatest vulnerability of the white matter occurs between 24 and 34 weeks of gestation and is related to the active growth of brain pathways. It is a phase of high proliferation, migration and maturation of glial cells. At this stage, axonal and dendritic growth, synapse formation and myelination are also occurring, as well as stabilization processes such as synaptic pruning, and specialization of circuits that reach their peak in the postnatal period at around two years of age (Marret et al., 2013; Semple et al., 2013). Thus, isolated white matter damage or combined gray and white matter abnormalities are frequent neuroimaging findings (Korzeniewski et al., 2008) as well as reduced total brain, cerebellum, and gray matter volumes in children with cerebral palsy (Kułak et al., 2016).

Due to early damage to the CNS, children often experience delays in the acquisition of motor skills, including delays in the appearance of primitive reflexes or their inhibition. Primitive reflexes are automatic involuntary movements that occur in response to a stimulus. In humans, satisfactory brain maturity is essential to allow the inhibition of primitive reflexes and the appearance of postural responses for the normal progression of psychomotor functions; this requires a transition from an involuntary brainstem reflex response to one controlled by the cortex. A child with delayed psychomotor development, as happens at CP, may demonstrate difficulties in motor performance such as locomotion and movement coordination, these being related to the greatest risk for abnormal development (Chandradasa and Rathnayake, 2020; Kobesova and Kolar, 2014). The control of these primitive reflexes is carried out at levels of sensorimotor control within the CNS with the cerebellum involved in all levels of integration, acting in muscle tone regulation, postural and balance maintenance (Kobesova and Kolar, 2014). This plays an important role of the cerebellum in the study of CP motor damage. These studies, however, are scarce.

Experimental studies have shown outcomes similar to what occurs in children with CP and its associated mechanisms. Animal models show that after insults during fetal or perinatal development, an inflammatory cascade and cellular apoptosis are triggered, leading to brain tissue damage and consequent deficiency in motor control, delay in appearance or inhibition of primitive reflexes, delay in the development of motor skills, loss of muscle mass (sarcopenia), muscle weakness, change in the distribution of muscle fiber types, dyskinesia, spasticity, hyperreflexia, culminating in functional deterioration (Shi et al., 2019; Zhang et al., 2016; Peterson et al., 2013; Gutman et al., 2011; Costa-de-santana et al., 2023; Lacerda et al., 2017a). Motor disorders are characteristic of children with CP (Peterson et al., 2013; Brandenburg et al., 2019) and they are often accompanied by disturbances of sensation, perception, cognition, communication and behavior (Brandenburg et al., 2019; Rosenbaum et al., 2007). Even the very survival of children is often related to the severity of functional disability (Gulati and Sondhi, 2017) and intellectual disability (Liptak et al., 2004).

In this context, CP models have advanced in the scientific literature to study this disease. Among these models of CP, the model of combined insults anoxia and sensorimotor restriction (SR) stands out for promoting changes similar to CP in children, such as neuromuscular damage (Strata et al., 2004a; da Silva et al., 2016; Calado et al., 2023a; da Silva et al., 2023). The isolated anoxia model determines most of the damage to the central nervous system but it promotes subtle and reversible damage to motor skills, especially locomotion and SR, contributes strongly to the deterioration maintenance of the motor function (da Conceição et al., 2021). Both, anoxia and SR cause damage to the CNS such as increased pro-inflammatory cytokines (Stigger et al., 2013) and oxidative stress in the cerebral cortex (da Silva et al., 2023), decreased neurogenesis in the hippocampus (Calado et al., 2023a; Takada et al., 2016), increased activated microglia in the hippocampus (Calado et al., 2023a) and cerebellum (Costa-de-santana et al., 2023), confirming the inflammatory cascade and excitotoxicity damage installed resulting from experimental model. Consequently, locomotion, motor coordination (da Conceição et al., 2021; Pereira et al., 2021; Coq et al., 2008; Marcuzzo et al., 2010; Strata et al., 2004b) posture, gait pattern (da Silva et al., 2023), masticatory function (Lacerda et al., 2017b; Lacerda et al., 2021), behavior and memory (Calado et al., 2023a; Takada et al., 2016) are impaired, causing a delay in the ontogenesis of developmental reflexes (Costa-de-santana et al., 2023). Thus, experimental models have proven to be important tools for elucidating the mechanisms underlying CP; from these, it is possible to investigate potential therapeutic interventions through phenotypic plasticity.

Phenotypic plasticity can be broadly defined as the ability of a genotype to produce different phenotypes in response to environmental conditions leading to changes in shape, state, movement or rate of activity (West-eberhard, 1986; West-eberhard, 2005). Various biotic and abiotic factors can induce phenotypic plasticity such as local environmental factors, chemical, social and hormonal changes (West-eberhard, 1986; Kelly et al., 2012; Turcotte and Levine, 2016). Among these factors, nutritional agents are strongly involved in recovery of CP model impairments, as observed in previous studies (da Silva et al., 2023; Lacerda et al., 2021; Calado et al., 2023b; Visco et al., 2022) and can be a resource to be used in CP during the critical period of development such as the neonatal period. However, current pharmacological and non-pharmacological treatments aim to minimize the limitation of the child's functionality and improve the comorbidities associated with CP but they are not able to reversing primary neuromuscular disorders.

Therapeutic perspectives that act both CNS and skeletal muscle damage have been highlighted such as resveratrol, included within the group of functional foods named polyphenols (Adefegha, 2018). Resveratrol, administered during the critical period of development, has shown promising effects in models of early brain injury and models of muscular atrophy. Resveratrol is known for its neuroprotective and antioxidant effects in several neurological disease models including models with implications for CP (Arteaga et al., 2014; Arteaga et al., 2015; Girbovan and Plamondon, 2015; Pan et al., 2016; Cai et al., 2018). Pre-treatment with resveratrol has been shown to prevent neuronal damage in the dentate gyrus and parietal cortex, reducing infarct volume, preserving myelination and minimizing the astroglial reactive response in a hypoxic-ischemia model (Arteaga et al., 2015). In post-treatment, resveratrol has also shown similar effects including reduction of the expression levels of key inflammatory factors (Pan et al., 2016). In a model of intracerebral hemorrhage, treatment with resveratrol was also reported to be beneficial in reducing neuronal damage in the hippocampus and decreasing the activation of microglia in the cortex (Cai et al., 2018). Further, in a model of cerebral ischemia reperfusion, a reduction in microglial activation was reported in the hippocampus (Girbovan and Plamondon, 2015). Regarding the effects of resveratrol on skeletal muscle, studies have shown the attenuation of denervation-induced muscle atrophy (Asami et al., 2018) and obesity-related muscle atrophy (Bai et al., 2020; Huang et al., 2019),

On the other hand, resveratrol has been highlighted in previous studies of in vitro models for its antioxidant effects on the cerebellum as well, directly related to muscular control. Resveratrol showed an antiapoptotic effect in apoptotic models in rat cerebellar granule neurons (CGNs) (an in vitro model of Parkinson's disease) (Alvira et al., 2007), as well as a neuroprotective effect on cerebellar granule neurons in models of ammonia (Bobermin et al., 2015) and ethanol neurotoxicity (Kumar et al., 2011). Resveratrol also appears to act in models of neurological disease that affect motor performance. Post-treatment with resveratrol evidently improved motor performance as well as muscle activity accompanied by a protection of Purkinje cells in ataxic rats (Ghorbani et al., 2018), in addition to benefits CP model in posture and behavior (Calado et al., 2023a; da Silva et al., 2023).

This makes resveratrol a possible treatment in CP models. Considering that studies on the effects of resveratrol have provided a new window of promising therapeutic action in CP, the present work aimed to investigate the effects of resveratrol neonatal treatment on neurodevelopment, skeletal muscle morphology and cerebellar damage in CP model. The hypothesis of this study was that resveratrol recovers cerebellum and musculoskeletal damage caused by CP model, reversing the damage to motor development.