Long-lasting recognition memory impairment and alterations in brain levels of cytokines and BDNF induced by maternal deprivation: effects of valproic acid and topiramate

Abstract

Exposure to stressful events early in life may have permanent deleterious consequences on nervous system function and increase the susceptibility to psychiatric conditions later in life. Maternal deprivation, commonly used as a source of neonatal stress, impairs memory in adult rats and reduces hippocampal brain-derived neurotrophic factor (BDNF) levels. Inflammatory cytokines, such as interleukins (IL) and tumor necrosis factor-α (TNF-α) have been shown to be increased in the peripheral blood of patients with psychiatric disorders. The aim of the present study was to investigate the effects of maternal separation on the levels of IL-10 and TNF-α, and BDNF in the hippocampus and prefrontal cortex of adult rats. We also evaluated the potential ameliorating properties of topiramate and valproic acid on memory deficits and cytokine and BDNF changes associated with maternal deprivation. The results indicated that, in addition to inducing memory deficits, maternal deprivation increased the levels of IL-10 in the hippocampus, and TNF-α in the hippocampus and in the cortex, and decreased hippocampal levels of BDNF, in adult life. Neither valproic acid nor topiramate were able to ameliorate memory deficits or the reduction in BDNF induced by maternal separation. The highest dose of topiramate was able to reduce IL-10 in the hippocampus and TNF-α in the prefrontal cortex, while valproate only reduced IL-10 levels in the hippocampus. These findings may have implications for a better understanding of the mechanisms associated with alterations observed in adult life induced by early stressful events, and for the proposal of novel therapeutic strategies.

Topiramate attenuates early brain injury following subarachnoid haemorrhage in rats via duplex protection against inflammation and neuronal cell death

“…With respect to TPM, its regulatory effect on inflammatory mediators has also been reported in prior research on CNS injuries. Utilizing rat pups with maternal deprivation, Pinheiro et al (2014) found that the administration of TPM at a high dosage reduced IL-10 levels in the hippocampus and TNF-α levels in the prefrontal cortex. Cure et al (2014) investigated the effect of oral TPM administration in rat models with live ischemia/ reperfusion injury and confirmed that TPM can decrease TNF-α and IL-6 levels in live tissues.…”

Effects of early-life adversity on immune function are mediated by prenatal environment: Role of prenatal alcohol exposure

“…Indeed, in rodents, maternal separation has been shown to decrease the number of microglial cells in the ventral tegmental area and substantia nigra (Chocyk et al, 2011) and, similar to our peripheral results, resulted in decreased central (IL-1β and IL-10) and peripheral (IL-1β and IL-6) cytokine levels (Dimatelis et al, 2012; Roque et al, 2016). This adversity-related suppression of immune function in infancy appears to sensitize the immune system in the long-term, resulting in an enhanced proinflammatory phenotype in later life, both in the periphery and the brain (Ganguly and Brenhouse, 2015; Hennessy et al, 2010; Nusslock and Miller, 2016; Pinheiro et al, 2015; Réus et al, 2013). Importantly, the preclinical and clinical literature has consistently shown that a chronic proinflammatory bias is associated with increased vulnerability to diseases/disorders later in life, including infections, cardiovascular disease, diabetes, cognitive and behavioral problems and mental health disorders (Bauman et al, 1997; Bilbo and Schwarz, 2009; Danese and McEwen, 2012; Meyer et al, 2009; Miller et al, 2011; Raison et al, 2006).…”

Neonatal binge alcohol exposure increases microglial activation in the developing rat hippocampus

“…Early life stress has been shown to alter cytokine expression in the neonatal and adult brain. Specifically, two studies using maternal separation stress from PD1–14 showed increased IL-1β concentrations in hippocampus on PD16 (no reported changes to IL-6 and TNF-α) (Roque et al, in press ) and upregulation of both IL-10 and TNF-α in the adult hippocampus (Pinheiro et al, 2015). Interestingly, this manipulation increased microglial activation and decreased number of astrocytes in the neonatal hippocampus (Roque et al, in press ).…”