Ebselen pretreatment attenuates ischemia/reperfusion injury and prevents hyperglycemia by improving hepatic insulin signaling and β-cell survival in gerbils

Abstract

Transient carotid artery occlusion causes ischemia/reperfusion (I/R) injury resulting in neuron and pancreatic β-cell death with consequential post-stroke hyperglycemia, which can lead to diabetes and may accelerate the development of Alzheimer's disease. Antioxidants have been shown to protect against the I/R injury and destruction of neurons. However, it is unknown whether the protection against I/R injury extends to the pancreatic β-cells. Therefore, we investigated whether treatment with ebselen, a glutathione peroxidase mimic, prevents neuronal and β-cell death following I/R in gerbils susceptible to stroke. After 28 days post artery occlusion, there was widespread neuronal cell death in the CA1 of the hippocampus and elevated IL-1β and TNF-α levels. Pretreatment with ebselen prevented the death by 56% and attenuated neurological damage (abnormal eyelid drooping, hair bristling, muscle tone, flexor reflex, posture, and walking patterns). Ischemic gerbils also exhibited impaired glucose tolerance and insulin sensitivity which induced post-stroke hyperglycemia associated with decreased β-cell mass due to increased β-cell apoptosis. Ebselen prevented the increased β-cell apoptosis, possibly by decreasing IL-1β and TNF-α in islets. Ischemia also attenuated hepatic insulin signaling, and expression of GLUT2 and glucokinase, whereas ebselen prevented the attenuation and suppressed gluconeogenesis by decreasing PEPCK expression. In conclusion, antioxidant protection by ebselen attenuated I/R injury of neurons and pancreatic β-cells and prevented subsequent impairment of glucose regulation that could lead to diabetes and Alzheimer's disease.

New Chiral Ebselen Analogues with Antioxidant and Cytotoxic Potential

“…Sec is the key element of the enzymes active site that provides GPx with the unique ability to reduce hydrogen peroxide and other reactive oxygen and nitrogen species [ 2 ]. This unique property makes ebselen a potent bioactive molecule which is effective in the treatment of various diseases including diabetes [ 3 , 4 , 5 , 6 ], Alzheimer’s disease [ 7 ], stroke [ 8 ], hearing loss [ 9 ], and cancer [ 10 ]. It is also non-toxic, as the selenium atom incorporated in its structure is not bioavailable [ 11 ].…”

Ebselen impairs cellular oxidative state and induces endoplasmic reticulum stress and activation of crucial mitogen‐activated protein kinases in pancreatic tumour AR42J cells

“…Therefore, it has been extensively employed as an anti-inflammatory and neuroprotective compound, notably in brain ischemia and stroke. 1,2 Beneficial effects of the cysteine-containing compound in other tissues and cellular systems have also been reported. For example, ebselen attenuates Mn-induced toxicity in Caenorhabditis elegans by preventing oxidative stress.…”

“…Its beneficial effects are mediated through its antioxidant and glutathione peroxidase‐mimetic properties, leading to attenuation of free radical generation, detoxification of free radicals and of the toxic products of their reactions. Therefore, it has been extensively employed as an anti‐inflammatory and neuroprotective compound, notably in brain ischemia and stroke . Beneficial effects of the cysteine‐containing compound in other tissues and cellular systems have also been reported.…”

Ebselen, a multi-target compound: its effects on biological processes and diseases

“…30) and tumour necrosis factor- α (TNF- α ) (Ref. 31). Alterations in the expression of these proteins affect apoptosis and oxidative stress.…”