Administration of an Acidic Sphingomyelinase (ASMase) Inhibitor, Imipramine, Reduces Hypoglycemia-Induced Hippocampal Neuronal Death

Abstract

Severe hypoglycemia (below 35 mg/dL) appears most often in diabetes patients who continuously inject insulin. To rapidly cease the hypoglycemic state in this study, glucose reperfusion was conducted, which can induce a secondary neuronal death cascade following hypoglycemia. Acid sphingomyelinase (ASMase) hydrolyzes sphingomyelin into ceramide and phosphorylcholine. ASMase activity can be influenced by cations, pH, redox, lipids, and other proteins in the cells, and there are many changes in these factors in hypoglycemia. Thus, we expect that ASMase is activated excessively after hypoglycemia. Ceramide is known to cause free radical production, excessive inflammation, calcium dysregulation, and lysosomal injury, resulting in apoptosis and the necrosis of neurons. Imipramine is mainly used in the treatment of depression and certain anxiety disorders, and it is particularly known as an ASMase inhibitor. We hypothesized that imipramine could decrease hippocampal neuronal death by reducing ceramide via the inhibition of ASMase after hypoglycemia. In the present study, we confirmed that the administration of imipramine significantly reduced hypoglycemia-induced neuronal death and improved cognitive function. Therefore, we suggest that imipramine may be a promising therapeutic tool for preventing hypoglycemia-induced neuronal death.

The Nox2-ROS-Nlrp3 Inflammasome Signaling Stimulates in the Hematopoietic Stem/Progenitor Cells Lipogenesis to Facilitate Membrane Lipid Raft Formation

“…Next, HSPCs were exposed to hematopoietic growth factors and cytokines cocktail [KL (1 ng/ml) + mIL-3 (1 ng/ml) + thrombopoietin (TPO, 5 ng/ml)] in serum-free medium for 1 h at 37 °C. Per each run, β2-microglobulin was used as an endogenous control *p < 0.05 and **p < 0.01 are considered statistically significant [37]. All these enzymes were upregulated in HSPCs stimulated with "cocktail of factors" that expand HSPCs such as KL + IL-3 + TPO, and by mainly pro-inflammatory factors including C3a, C5a, and eATP.…”

The Inhibition of Zinc Excitotoxicity and AMPK Phosphorylation by a Novel Zinc Chelator, 2G11, Ameliorates Neuronal Death Induced by Global Cerebral Ischemia

“…GCI also disrupted blood–brain barrier (BBB) integrity as seen in focal ischemia, hypoglycemia, head trauma, and multiple sclerosis. When BBB breakdown occurs, the activation of non-neuronal cells, microglia, and the astrocytes and extravasation of brain substrates such as immunoglobulin are induced [ 15 , 57 , 58 ]. Ischemic stroke-induced BBB damage also increases the activation of matrix metalloproteinase-9 (MMP-9) [ 59 , 60 ], which is associated with tight junction components, resulting in a disruption of BBB integrity [ 61 ].…”

Acid Sphingomyelinase Inhibitor, Imipramine, Reduces Hippocampal Neuronal Death after Traumatic Brain Injury

“…TBI-induced neuronal death is caused by zinc accumulation, oxidative stress, excitotoxicity, and inflammation [ 37 , 38 , 39 ]. The results of our previous studies have demonstrated that TBI increased the release of vesicular zinc from the presynaptic terminals [ 35 , 40 , 41 ]. Thus, we think that presynaptically released zinc can activate ASMase and then increase ceramide production, which later induces a neuron death cascade after TBI.…”

“…To avoid shivering following hypothermia, we consistently maintained the animal’s body temperature at 36–37.5 °C using a heating pad. We immediately intraperitoneally injected imipramine (10 mg/kg, dissolved in 0.9% normal saline, once) after termination of TBI [ 35 , 65 , 66 , 67 ] ( Figure 7 ).…”

“…Furthermore, imipramine is used to protect neurons from inflammation and apoptosis [ 31 , 32 ]. Imipramine has a neuroprotective effect via the inhibition of ASMase in transient global ischemia and hypoglycemia [ 33 , 34 , 35 ].…”