Tanshinone I alleviates motor and cognitive impairments via suppressing oxidative stress in the neonatal rats after hypoxic-ischemic brain damage

Introduction Perinatal hypoxia‐ischemia (HI) is one of the main causes of mortality and chronic neurological morbidity in infants and children. Astrocytes play a key role in HI progression, becoming reactive in response to the injury, releasing S100 calcium binding protein B (S100B). Since S100B inhibition seems to have neuroprotective effects on central nervous system injury models, here we evaluated the neuroprotective effects of an S100B inhibitor, arundic acid (AA) in a HI model. Methods On the 7th postnatal day, animals were submitted to the combination of common carotid artery occlusion and hypoxic atmosphere (8% O2) for 60 min. Three experiments were performed in order to: (1) define AA dose (0.1, 1 or 10 mg/kg, pre‐hypoxia i.p. injection), (2) test if repeated AA administrations (10 mg/kg at 3 time points: Pre‐hypoxia, 24 h and 48 h after HI) would improve the response and (3) investigate biochemical mechanisms involved in AA protection two days after HI. Results AA at a dose of 10 mg/kg applied before and after hypoxia, was the only treatment protocol that was able to improve HI‐induced memory deficits, to reduce tissue damage, to promote astrocytic survival in the hippocampus and to reduced extracellular release of S100B in the cerebrospinal fluid. Conclusion Overall, AA treatment showed beneficial effects on memory deficits, tissue damage, promoting astrocyte survival likely by reducing S100B release. Protection aided to astrocytes by AA treatment against HI lesion may lead to development of new therapeutic strategies that target these particular cells.

Section: Discussionsupporting

confidence: 46%

Section: Discussionmentioning

confidence: 49%

Arundic acid administration protects astrocytes, recovers histological damage and memory deficits induced by neonatal hypoxia ischemia in rats

Mari

Odorcyk

Sanches³

et al. 2019

“…The Levine‐Rice model of neonatal HI provides a valuable experimental approach to reproduce the long term tissue brain damage and behavioral consequences of human hypoxia ischemia. HI rats show cognitive disabilities, with males being more susceptible to tissue loss in structure such as the CA1 area of hippocampus, a critical region for cognitive tasks (Arteni et al, 2010; Dai et al, 2017; Netto et al, 2017). Long‐term assessment of cognitive impairment, at 60 postnatal days and 90 postnatal days, has been reported after experimental neonatal HI (Arteaga et al, 2015; Sanches et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Phytoestrogen coumestrol attenuates brain mitochondrial dysfunction and long‐term cognitive deficits following neonatal hypoxia–ischemia

Anastácio

Sanches

Nicola

et al. 2019

Introduction: Neonatal Hypoxia-Ischemia (HI) is a major cause of morbidity and mortality, and is frequently associated with short and long-term neurologic and cognitive impairments. The HI injury causes mitochondrial damage leading to increased production of reactive oxygen species (ROS). Phytoestrogens are non-steroidal plant substances structurally and functionally similar to estrogen. Coumestrol is a potent isolavonoid with a protective efect against ischemic brain damage in adult rats. Our aim was to determine if coumestrol treatment following neonatal HI attenuates the long-term cognitive deicits induced by neonatal HI, as well as to investigate one possible mechanism underlying its potential efect. Methods: On the 7th postnatal day, male Wistar rats were submitted to the Levine-Rice HI model. Intraperitoneal injections of 20 mg/kg of coumestrol, or vehicle, were administered immediately pre-hypoxia or 3 h post-hypoxia. At 12 h after HI the mitochondrial status and ROS levels were determined. At 60th postnatal day the cognitive deicits were revealed in the Morris water maze reference and working spatial memories. Following behavioral analysis, histological assessment was performed and reactive astrogliosis was measured by GFAP expression. Results: Results demonstrate that both pre-and post-HI administration of coumestrol were able to counteract the long-term cognitive and morphological impairments caused by HI, as well as to block the late reactive astrogliosis. The pre-HI administration of coumestrol was able to prevent the early mitochondrial dysfunction in the hippocampus of injured rat pups. Conclusion: Present data suggest that coumestrol exerts protection against experimental neonatal brain hypoxiaischemia through, at least in part, early modulation of mitochondrial function.

“…It has been well documented that the impairment of learning and memory is the major sequelae of HIE in human and a variety of animal models of hypoxia (Dai et al, 2017). Long‐lasting cognitive consequences of neonatal hypoxia/HI include deficits in spatial learning and memory (Takada et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Oxidative stress plays an important role in neuronal damage both in animal models of neonatal hypoxia and reoxygenation and in babies suffering from birth asphyxia (Caputa et al, 2005). An inhibition of oxidative stress may be a potential therapeutic for HIE (Dai et al, 2017; Zhang et al, 2018). It has been shown earlier that NADA exerts antioxidant and neuroprotective activities in different experimental models through mechanisms that are independent of CB1 and TRPV‐1 receptors (Bobrov et al, 2008; Grabiec et al, 2012; Novosadova et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Early‐life N‐arachidonoyl‐dopamine exposure increases antioxidant capacity of the brain tissues and reduces functional deficits after neonatal hypoxia in rats

Sukhanova

Sebentsova

Khukhareva

et al. 2019

Perinatal hypoxia‐ischemia is one of the most common causes of perinatal brain injury and subsequent neurological disorders in children. The aim of this work was to evaluate the potential antioxidant and neuroprotective effects of N‐arachidonoyl‐dopamine (NADA) in the model of acute neonatal hypoxia (ANH) in rat pups. Male and female Wistar rats were exposed to a hypoxic condition (8% oxygen for 120 min) at postnatal day 2 (P2). Transcription factor HIF1‐α and glutathione peroxidases GPx2 and GPx4 gene expression was increased in rat brains in the hypoxic group compared to control 1.5 h but not 4 days after ANH. There were no post‐hypoxic changes in reduced (GSH) and oxidised (GSSG) glutathione levels in the brain of rat pups 1.5 h and 4 d after hypoxia. Hypoxic rats displayed retarded performance in the righting reflex and the negative geotaxis tests. ANH resulted in increased ambulation in Open field test and impaired retention in the Barnes maze task under stressful conditions as compared with the control group. Treatment with NADA significantly attenuated the delayed development of sensorimotor reflexes and stress‐evoked disruption of memory retention in hypoxic rats but had no effect on the hypoxia‐induced hyperactivity. In rats exposed to hypoxia, treatment with NADA decreased GPx2 gene expression and increased GSH/GSSG ratio in whole brains 1.5 h after ANH. These results suggest that the long‐lasting beneficial effects of NADA on hypoxia‐induced neurobehavioural deficits are mediated, at least in part, by its antioxidant properties.