Research reportNeuroprotective actions of taurine on hypoxic-ischemic brain damage in neonatal rats
Graphical abstract
Introduction
Neonatal hypoxic-ischemic brain damage (HIBD) is a relatively common malignant complication caused by clinical perinatal asphyxia in infants and young children (Chen et al., 2015, Thatipamula et al., 2015), which occurs in 1–6 of every 1000 live term births (Gu et al., 2016, Koonrungsesomboon et al., 2014). Statistics suggests that approximately 40% of the affected infants die in the neonatal period and an additional 30% have lifelong neurological deficits including cerebral palsy, epilepsy and cognitive disabilities (Hristova et al., 2016). The treatment and care for the sequelae of HIBD require extensive resources. What is unfortunate is that current treatment regimens are not optimal, even remained ineffective. Moreover, even with the best care, these children only have little improvement in the overall ability. Accordingly, HIBD is a major public health issue which globally leads to substantial socio-economic burden of the individual, family and healthcare system (Ding et al., 2016). Altogether, efficient pharmacological strategies for the sanitation and therapy of HIBD are restricted by safety and toxicity considerations. Given the magnitude of the problem, it is urgent and unmet to focus on how to supply safe and effective neuroprotective medicine, which would promote prognosis of HIBD infants by promoting after-injury repair.
Although the precise pathogenesis of HIBD is still inconclusive, it is valid that oxidative stress, oxidative metabolism and apoptosis are the significant components of cell death following HIBD (Taylor et al., 1999, Ding et al., 2016). Oxidative stress and oxidative metabolism play a pivotal role in the procedure of pathogenesis after the occurrence of HIBD which ultimately trigger cell death. Additionally, on account of the immature brains possess fairly high polyunsaturated fatty acid concentration, meanwhile low concentration of antioxidants, they are considered to be particularly prone to tissue damage due to oxidative stress after hypoxia-ischemia injury (Zhang et al., 2014). Pathological accumulation of excessive reactive oxygen species (ROS) and subsequent oxidative stress results in brain necrosis and apoptosis (Chang et al., 2016). Endogenous antioxidants such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), possess the ability of scavenging overproduction of oxidants to prevent deleterious ROS generation (Chen et al., 2015, Zhao et al., 2015).
Apoptosis is a form of cellular suicide which is essential for development and tissue homeostasis of all metazoan organisms (Guo et al., 2002). Mitochondrion as a key organelle is the main source of cellular ATP which may also regulate cell death (Granville et al., 2001). It is demonstrated that mitochondria are involved in cell death based on experimental stroke (Sun et al., 2011). A mechanism pertaining to the death of immature neurons is the accumulation of AIF and Cyt c, which is safely sequestered within the mitochondrial intermembrane space in non-apoptotic cells (Guo et al., 2002). On the other hand, anti-apoptotic protein Bcl-2, also known as a mitochondrial membrane protein, blocks the apoptotic death of many cell types (Taylor et al., 1999; Gu et al., 2016), it plays a crucial role in regulation of mitochondria-mediated cell death. Therefore, anti-apoptotic therapies via inhibiting AIF and Cyt c expression and modulating the actions of Bcl-2 family proteins have been proposed to be useful in ameliorating neonatal HIBD.
Taurine, a β-amino acid, presents high concentration in the mammalian tissues, which possesses a number of cytoprotective properties through its actions as neurotransmitter, neuromodulator, osmoregulator, anti-oxidant, membrane stabilizer, anti-inflammation and neuroprotection (El Idrissi, 2008, Schuller-Levis and Park, 2004, Haas and Hosli, 1973, Hussy et al., 1997, Huxtable, 1989, Huxtable, 1992). In recent years, taurine has been demonstrated to function neuroprotective activity in various kinds of in vitro and in vivo brain injury models. It has been reported that taurine reduces caspase-8 and caspase-9 expression in ischemia injury (Taranukhin et al., 2008) and intracellular calcium elevation, as well as depresses calpain activation, thereby attenuating glutamate-induced apoptotic neuronal death and enhancing Bcl-2:Bax ratio. Furthermore, in vivo taurine has been verified to protect brain against experimental stroke in a dose dependent manner with marked protection (Sun et al., 2011, Sun et al., 2012a, Sun et al., 2012b, Wang et al., 2007).
However, no information is available on possible effects of taurine in neonatal brain injury induced by hypoxia-ischemia. It was speculated that taurine might exert a protective effect on neonatal HIBD under this background. To test the hypothesis, the present experiment was designed to investigate the potential neuroprotective effects of post-insult administration of taurine on neonatal HIBD using the neonatal hypoxic-ischemic rat model as well as to further identify its underlying mechanisms.
Section snippets
Experiment animals
Female Sprague-Dawley rats with 7-day-old neonates were supplied by the Experimental Animal Center of Ningxia Medical University (Certificate number was SYXK Ningxia 2015-0001). The animals were housed in the temperature-controlled environment (22–24° C) under 12 h light and dark cycles and animals had access to food and water ad labium. The experimental designs and all procedures were in accordance both with the National Guidelines for Care and Use of Laboratory Animals, together with the Animal
TTC staining
Representative coronal brain sections from vehicle and taurine-treated rats stained with 1% TTC are illustrated in Fig. 1A, normal brain tissues appeared uniform red while the infarction region showed white. There was no remarkable cerebral infarct area in the sham-operated group rats, and post-treatment with taurine (30, 60 and 120 mg/kg) group significantly reduced the percentage of infarction to 21.43 ± 1.84% (P < 0.05), 17.10 ± 2.88% (P < 0.01), 10.93 ± 1.65% (P < 0.01) when versus the HI group 24.09 ±
Discussion
Some researchers have reported protective functions of taurine against experimental stroke through preserving the mitochondrial functions and blocking the mitochondria-mediated cell death pathway in the penumbra and core. In view of these findings of neuroprotective effect of taurine on adult rats, we investigated the hypothesis of the potential neuroprotective effect of taurine on the brain injury due to HIBD. Using TTC staining in the present study, we proved that post-treatment of taurine
Conclusions
Our data demonstrate that the post-treatment of HIBD in neonatal rats with taurine exerts significant neuroprotective effect. Taurine treatment exhibits remarkably reduced infarct volume and suppressed cell death. Histopathology injury is ameliorated, antioxidant enzyme activities are increased and lipid peroxide is alleviated. In addition, the levels of ATP, lactic acid and MPO are decreased. The inhibition of AIF and Cyt C expression, together with the modulation of the actions of Bcl-2
Conflict of interest statement
The authors declare that they have no conflicts of interest.
Acknowledgment
The authors gratefully acknowledge the financial supported by the Ningxia Hui Autonomous Region Science and Technology Support Program (2015BAK45B01).
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These authors contributed equally to this work.