Midazolam Activates the Intrinsic Pathway of Apoptosis Independent of Benzodiazepine and Death Receptor Signaling

Abstract

Midazolam induces apoptosis via activation of the mitochondrial pathway in a concentration-dependent manner. The mechanism of midazolam toxicity switches from caspase-dependent apoptosis to necrosis with increasing concentrations. The induction of apoptosis and necrosis by midazolam is presumably unrelated to GABAA receptor pathway signaling.

Midazolam Inhibits the Apoptosis of Astrocytes Induced by Oxygen Glucose Deprivation via Targeting JAK2-STAT3 Signaling Pathway

“…In this current study, we firstly demonstrated that midazolam could inhibit apoptosis of brain astrocytes cultured under oxygen glucose deprivation condition via targeting. However, in another study, Gaza et al have demonstrated that midazolam could induce human lymphoma and neuroblastoma cell lines apoptosis via activation of the mitochondrial in a concentration-dependent manner [40]. Thus, there are numerous mechanisms by which midazolam can potentially act to protect the brain against ischemic injury or to induce human lymphoma and neuroblastoma cell lines apoptosis.…”

The Influence of Adjuvants Used in Regional Anesthesia on Lidocaine-Induced Neurotoxicity In Vitro

“…46,55Y57 As with lidocaine before, we demonstrated that midazolam induces apoptosis via activation of the intrinsic pathway. 10 Therefore, it is not astonishing that midazolam enhances lidocaine-induced apoptosis. In contrast to ketamine, this effect was subadditive for unknown reasons.…”

“…Toxicities of ketamine and midazolam alone were described previously in our model. 9,10 Concentrations of additives were calculated from doses used clinically when coadministered with local anesthetics intrathecally. For example, a clinically used morphine solution will most often contain 10 mg/mL (26,600 KM), and a recommended single dose of 0.25 to 0.5 mg would typically be further diluted to 0.06 to 0.12 mg/mL in a volume of 4 mL (160Y320 KM) before injection.…”

“…7 Similarly, ketamine and midazolam were re-ported to induce apoptosis by activation of the mitochondrial pathway. 9,10 Because these substances all induce toxicity via the same pathway, one might presume that toxicities of ketamine and midazolam further enhance the toxicity of lidocaine.…”

“…Recently, we demonstrated that lidocaine, ketamine, and midazolam all induce apoptosis via the mitochondrial pathway and are toxic in neuronal and glial cells in a concentration-dependent manner. 7,9,10,15 Thus, we hypothesized that ketamine and midazolam increase the toxicity of lidocaine at least in an additive manner. Therefore, we used our established model of local anesthetic-induced toxicity to study the possible additive toxicity of morphine, sufentanil, clonidine, epinephrine, neostigmine, ketamine, and midazolam when added to a toxic concentration of lidocaine.…”