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 with a number of functional repercussions in the organism (Pereira et al., 2021; Fragopoulou et al., 2019; Jacobsson and Hagberg, 2004). Due to the complexity of its aetiology, its causes are not fully understood. Brain injuries in the neonatal and perinatal period are known to contribute to CP development, including asphyxia, hypoxia-ischemia and infections (Fragopoulou et al., 2019; McIntyre et al., 2022; Jacobsson and Hagberg, 2004; Blair and Stanley, 2002). These trigger a cascade of functional consequences (Fragopoulou et al., 2019)1. Given the alterations and damages present in CP, it has been the subject of a number of studies: pre-clinical studies have pointed to a relationship between the lesions and brain alterations present in CP and their impact on behaviour, especially in locomotion (Pereira et al., 2021), where it is possible to observe a delay in the acquisition of motor skills (Krigger, 2006; Ward et al., 2006; Mockford and Caulton, 2010; Peterson et al., 2013; Coq et al., 2008) and in motor coordination and movement (Coq et al., 2008; Pereira et al., 2021), causing functional impairments of various aspects of locomotion (Pereira et al., 2021).

Thus, the CP is understood as a set of syndromes that cause impairments in the movement and posture of affected children (Marret et al., 2013; Rumajogee et al., 2016). Nevertheless, sensory-perceptual abnormalities are also found in association with CP, impairing cognitive abilities such as memory (Hirsh et al., 2010; Al-Nemr and Abdelazeim, 2017; Pirila et al., 2004; Pueyo et al., 2009; White and Christ, 2005). For this reason, a high prevalence of learning problems is observed, in approximately about 40% of children with CP (Himmelmann et al., 2006; Van Rooijen et al., 2015). Memory and fine motor movement impairments are associated with low school performance in children with CP (Van Rooijen et al., 2015).

The development of CP is multifactorial and may occur after brain lesions in prenatal, perinatal and postnatal periods (Graham et al., 2019). The main risk factors for the emergence of CP are closely linked to events that occur in the foetal and neonatal period, such as foetal growth restriction, multiple pregnancies, birth asphyxia and, above all, premature birth, which is still considered the main risk factor for the development of CP (Graham et al., 2019; Oskoui et al., 2013; Stavsky et al., 2017). Due to the number and complexity of events that can trigger the onset of CP, it is considered the most common cause of physical disability in childhood (Himmelmann, 2013; Yeargin-Allsopp et al., 2008), affecting about 3,4 per 1000 live births in regions from low-income countries and 1,5 per 1000 live births in regions from high-income countries (McIntyre et al., 2022), thus pointing to the relevance of obstetric care.

However, recent preclinical studies have pointed to impairments beyond the neuromotor sequelae, observing an increase in depressive and anxiogenic behaviours (Herrera et al., 2018; Granja et al., 2021) and a reduction in memory performance (Granja et al., 2021; Matsuda et al., 2021) in early brain lesion models. This difficulty in forming and retrieving new memories can be associated with reported damages in the brain areas related to emotional behaviour and memory, such as the frontal cortex and hippocampus (Granja et al., 2021; Visco et al., 2021; Basilious et al., 2014; Matsuda et al., 2021). The hippocampus can be understood as a structure sensitive to neuroinflammation and asphyxia in the perinatal period, showing a reduction in neurogenesis and a significant increase in neurodegeneration, accompanied by severe behavioural and memory alterations (Granja et al., 2021; Visco et al., 2021; Basilious et al., 2014; Matsuda et al., 2021). Among the most present alterations, there is damage to the cornu ammonis 1 (CA1) and 3 (CA3) and the dentate gyrus (DG) of the hippocampus, reflected in changes in memory formation especially short-term spatial memory and reference memory (Matsuda et al., 2021; Takada et al., 2016). Also, in these previous studies, the literature reported that perinatal brain damage affected neurogenesis after birth in key brain regions such as the hippocampus and subventricular zone (Visco et al., 2021). For this reason, early brain injury affects hippocampal maturation and impairs memory formation.

The first years of life, this perinatal period, represent a crucial phase for development, with consequences on both the physiological systems and behaviour (Kelly et al., 2012; Anderson et al., 2011). The effects of hypothermia on memory are not yet fully understood, because memory have not yet matured in this early period; there are some disagreements about its long-term repercussion (Cainelli et al., 2021). In this context, various types of interventions are currently being studied to mitigate functional impairments in individuals with brain injuries, hypothermia is commonly used in children with brain injuries because can impede the extent of brain infarct (Wagner et al., 2002). Hypothermia can reduce oxidative stress and inhibit the release of pro-inflammatory cytokines after brain injury (Talma et al., 2016), as well as reduce neurodevelopmental damage in newborns (Azzopardi et al., 2014) and also reduce the risk of mortality in neonates, becoming an acute therapeutic strategy investigated in clinical and preclinical studies (Cainelli et al., 2021; Azzopardi et al., 2014; Shankaran et al., 2012).

In this context, despite advances in perinatal care to reduce mortality and functional consequences, there are still few therapeutic strategies that address the central problem of CP as a brain injury for clinical use. As well, there are reported few strategies to attenuate the damage and memory formation disturbances in subjects with brain lesions. Given the annual increase in cases of CP and brain lesions cases, we questioned: what are the treatment prospects for memory formation problems during lifespan in subjects with CP? Thus, the aim of this review is to map and analyse the effects of the main used in the treatment of memory formation problems and hippocampal damage present in adult animals that were subjected to brain damage during the perinatal period with implications for the development of cerebral palsy.

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