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

Abstract

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.

S100B Protein as a Therapeutic Target in Multiple Sclerosis: The S100B Inhibitor Arundic Acid Protects from Chronic Experimental Autoimmune Encephalomyelitis

“…Indeed, the biomolecular evaluation of S100B in brain tissue showed intriguingly that the protein was not reduced as compared to in the control animals. Similar results were obtained after the administration of AA in neonatal rats where experimental hypoxia ischemia was induced [33]. This result was obtained in whole tissue extracts, where the evaluation of S100B expression in individual cells could not be assessed.…”

“…Using experimental animal models, AA has also been shown to improve other neural disorders, such as Alzheimer's disease [25], Parkinson's disease [26], acute brain, and spinal cord injury [14,19,[27][28][29][30][31][32][33]. In these cases, its effect has been essentially attributed to the inhibition of astrocytic S100B synthesis [14,27].…”

Growing role of S100B protein as a putative therapeutic target for neurological- and nonneurological-disorders

“…In addition, in rats prone to spontaneously hypertensive stroke, AA has been shown to prevent hypertension-induced stroke, and to inhibit the enlargement of the stroke lesion by counteracting S100B overproduction in inflammation-activated astrocytes(Higashino et al, 2009). In neonatal rats, AA has also been shown to recover tissue damage and memory deficits induced by hypoxia ischemia(Mari et al, 2019). In addition, genetic ablation of S100B using S100B knockout mice(Kabadi et al, 2015), or RNA interference-mediated silencing of S100B(Zhang et al, 2018), have produced functional and neuropathological amelioration in mice subjected to experimental traumatic brain injury, and in rats with ischemic stroke.…”

Preterm Brain Injury, Antenatal Triggers, and Therapeutics: Timing Is Key

“…In the context of neonatal HI induced brain injury, astrogliosis is observed with reactive astrocytes exhibiting swollen end-feet [ 120 , 121 , 122 ]. Moreover, marked astrogliosis was observed at three and seven days after global HI in ovine fetal models [ 62 , 123 , 124 ].…”