All-Trans-Retinoic Acid Rescues Neurons After Global Ischemia by Attenuating Neuroinflammatory Reactions

Abstract

Retinoic acid (RA) plays an important role in the developing mammalian nervous system. Based on this concept, some studies have demonstrated the beneficial effects of RA administration on neurogenesis in neuropathological diseases. Some investigations have revealed the anti-inflammatory effects of RA treatment in multiple systems, in addition to its role in neurogenesis. To date, however, the neuroprotective efficacy of RA after cerebral ischemia, especially in the context of its anti-inflammatory effects, has been poorly demonstrated. Additionally, to the best of our knowledge, experiments of the therapeutic efficacy of RA treatment in a transient global ischemic model in the Mongolian gerbil have been lacking worldwide. Here, we studied the neuroprotective effects and neurobehavioral outcomes of intraperitoneally administered all-trans-RA (ATRA; a synthetic form of RA) on brains with transient global ischemia that was induced with the bilateral common carotid artery occlusion and reperfusion (BCCAO/R) model in the gerbil. In order to identify whether these neuroprotective mechanisms were due to the anti-inflammatory effects of ATRA, in vivo hippocampal expression of proinflammatory cytokines including tissue necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) after ATRA injection and in vitro levels of release of nitric oxide, TNF-α and IL-6 from lipopolysaccharide (LPS)-stimulated BV2 microglial cells after ATRA treatment were evaluated. The results showed that ATRA can protect pyramidal neurons in the hippocampal CA1 region against BCCAO-induced neuronal apoptosis and significantly reduce the extent of astrocytosis and microglial activation. In addition, the ischemia-induced neurobehavioral changes were normalized by ATRA injection. Consistent with these phenotypic data, we observed the diminishing effects of ATRA treatment on the production of proinflammatory mediators (e.g., TNF-α and IL-6) in hippocampal homogenates and LPS-stimulated BV2 cells, and these effects were dose-dependent. These results suggest a beneficial role of ATRA in the attenuation of global cerebral ischemia due to its anti-inflammatory properties, resulting in, at least partly, the inhibition of microglial secretion of variable proinflammatory cytokines.

All‐trans retinoic acid protects against doxorubicin‐induced cardiotoxicity by activating the ERK2 signalling pathway

“…However, its effectiveness is limited, and its long‐term benefits are unclear (Wiseman et al , ; Schlitt et al ., ). The unique biological profile of ATRA has attracted considerable interest for many years, and it has been shown to have both neuro and hepatic protective effects (Nagy, ; Kim et al ., ). In the present study it was revealed that ATRA can protect against doxorubicin‐induced cardiotoxicity.…”

“…ATRA exhibits not only anticancer effects (Mangiarotti et al ., ; Liu et al ., ; Rosenberg et al ., ; Long et al ., ) but also acts as a new class of cardioprotective agent (Bernard et al ., ; Guleria et al ., ; Kim et al ., ). The results of this study also raise the possibility that ATRA may have therapeutic potential to protect the heart against the toxicity of cancer chemotherapies, suggesting that these compounds, like vincristine (Chatterjee et al ., ), deserve further extensive pharmacology and preclinical investigations.…”

“…Retinoic acid derivatives are essential for tissue homeostasis, cellular proliferation (Wiggert et al ., ) and the prevention of various diseases, such as neurotoxicity (Cheng et al ., ; Kim et al ., ), hepatitis and hepatic ischaemia (Rao et al ., ; Nagy, ). All‐trans retinoic acid (ATRA) protects cardiomyocytes from various stimuli by inhibiting oxidative stress, preventing cardiomyocyte apoptosis and attenuating p38 MAPK, JNK and NF‐κB activation (Choudhary et al ., ; Lou et al ., ; Nizamutdinova et al ., ).…”

Characterization of neural stem cells and their progeny in the sensory circumventricular organs of adult mouse

“…This observation is in good agreement with the previous study that LPS stimulation attenuates proliferation of OPCs in the amygdala and hippocampus (Wennström et al 2014). This is exemplified by the evidence that stereotactic intracranial injections with LPS increase hippocampal neurogenesis (Kim et al 2013), while systemically administered LPS decreases neurogenesis (Ekdahl et al 2003;Monje et al 2003). Neonatal inflammation influences reactivity to stress, immune regulation, susceptibility to disease, and memory impairment in adulthood (Shanks et al 2000).…”

Intermittent fasting is neuroprotective in focal cerebral ischemia by minimizing autophagic flux disturbance and inhibiting apoptosis

“…Neuronal death induced by cerebral ischemia is a major cause of high morbidity and mortality (1). Although previous studies have yielded encouraging results when investigating therapeutic candidates using animal models of cerebral ischemia (2,3), no pharmacological strategies are currently effective in the clinical setting.…”