Mechanisms Underlying Midazolam-Induced Peripheral Nerve Block and Neurotoxicity

Yılmaz, Esra Karabağ; Hough, Karen A.; Gebhart, G. F.; Williams, Brian A.; Gold, Michael S.

doi:10.1097/aap.0000000000000176

Cited by 15 publications

(13 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Preservatives added to steroids such as benzyl alcohol and propylene glycol have known neurolytic effects, so it is important to avoid steroid adjuvants with any preservatives (preservative-free dexamethasone sodium phosphate is recommended by the authors). Midazolam, acting primarily as a GABA-A agonist, was previously thought to attenuate nerve blockade by acting at peripheral GABA-A receptors 19 , although this more recently has been attributed to TSPO activation 7 .…”

Section: Clonidine-buprenorphine-dexamethasonementioning

confidence: 99%

“…Steroids, such as dexamethasone, have systemic anti-nausea and anti-nociceptive effects, with possible decreased C-fiber transmission with perineural administration 6 . Midazolam, primarily known as a GABA-A agonist, may have similar pain modulation effects by acting as an agonist in the periphery via the 18 kilodalton translocator protein (TSPO) 7 , formerly known as the “peripheral benzodiazepine receptor.”…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Neurotoxicity of common peripheral nerve block adjuvants

Knight

Schott²,

Kentor³

et al. 2015

Current Opinion in Anaesthesiology

Self Cite

View full text Add to dashboard Cite

Purpose of Review Outline the analgesic role of perineural adjuvants for local anesthetic nerve block injections, and evaluate current knowledge regarding whether adjuvants modulate the neurocytologic properties of local anesthetics. Recent Findings Perineural adjuvant medications such as dexmedetomidine, clonidine, buprenorphine, dexamethasone, and midazolam play unique analgesic roles. The dosing of these medications to prevent neurotoxicity is characterized in various cellular and in vivo models. Much of this mitigation may be via reducing the dose of local anesthetic used while achieving equal or superior analgesia. Dose-concentration animal models have shown no evidence of deleterious effects. Clinical observations regarding blocks with combined bupivacaine-clonidine-buprenorphine-dexamethasone have shown beneficial effects on block duration and rebound pain without long-term evidence of neurotoxicity. In vitro and in vivo studies of perineural clonidine and dexmedetomidine show attenuation of perineural inflammatory responses generated by local anesthetics. Summary Dexmedetomidine added as a peripheral nerve blockade adjuvant improves block duration without neurotoxic properties. The combined adjuvants clonidine, buprenorphine, and dexamethasone do not appear to alter local anesthetic neurotoxicity. Midazolam significantly increases local anesthetic neurotoxicity in vitro, but when combined with clonidine-buprenorphine-dexamethasone (sans local anesthetic) produces no in vitro or in vivo neurotoxicity. Further larger-species animal testing and human trials will be required to reinforce the clinical applicability of these findings.

show abstract

Section: Clonidine-buprenorphine-dexamethasonementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neurotoxicity of common peripheral nerve block adjuvants

Knight

Schott²,

Kentor³

et al. 2015

Current Opinion in Anaesthesiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…It produces central nervous system depression effects through the stimulation of γ-amino butyric acid receptors (5). To date, midazolam remains the predominant intensive care unit (ICU) sedative agent (6).…”

Section: Introductionmentioning

confidence: 99%

Dexmedetomidine versus midazolam for sedation during endoscopy: A meta-analysis

Zhang

Sun

Zheng

et al. 2016

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

Patients undergoing endoscopy frequently require sedation, which commonly includes the administration of midazolam or dexmedetomidine. Previous meta-analyses have mainly focused on comparing the effects of these two drugs in intensive care unit patients. In the present study, randomized controlled trials (RCTs) that compared the sedative and clinical effectiveness of these two drugs in patients undergoing endoscopy were searched in a number of databases. The meta-analysis showed that dexmedetomidine demonstrated a significantly lower rate of respiratory depression and adverse events compared with those presented upon midazolam administration. A significant difference was also observed in the sedation potency of the sedatives. The current controlled data suggest that dexmedetomidine may be an alternative to midazolam in the sedation for endoscopy. However, more high-quality and well-designed studies are required to further evaluate this conclusion.

show abstract

“…Previous studies on sedative drugs’ effects have mainly focused on its clinical dosages and side effects, 29 , 30 and some investigations have indicated that midazolam could induce neurotoxicity. 31 A recent study showed that midazolam can induce cancer cell apoptosis. 32 In fact, our earlier studies have shown that midazolam could briefly induce MA-10 mouse Leydig tumor cell apoptosis by activating caspase and MAPK pathways.…”

Section: Discussionmentioning

confidence: 99%

Midazolam regulated caspase pathway, endoplasmic reticulum stress, autophagy, and cell cycle to induce apoptosis in MA-10 mouse Leydig tumor cells

Chen

Wang

et al. 2016

OTT

View full text Add to dashboard Cite

PurposeMidazolam is widely used as a sedative and anesthetic induction agent by modulating the different GABA receptors in the central nervous system. Studies have also shown that midazolam has an anticancer effect on various tumors. In a previous study, we found that midazolam could induce MA-10 mouse Leydig tumor cell apoptosis by activating caspase cascade. However, the detailed mechanism related to the upstream and downstream pathways of the caspase cascade, such as endoplasmic reticulum (ER) stress, autophagy, and p53 pathways plus cell cycle regulation in MA-10 mouse Leydig tumor cells, remains elusive.MethodsFlow cytometry assay and Western blot analyses were exploited.ResultsMidazolam significantly decreased cell viability but increased sub-G1 phase cell numbers in MA-10 cells (P<0.05). Annexin V/propidium iodide double staining further confirmed that midazolam induced apoptosis. In addition, expressions of Fas and Fas ligand could be detected in MA-10 cells with midazolam treatments, and Bax translocation and cytochrome c release were also involved in midazolam-induced MA-10 cell apoptosis. Moreover, the staining and expression of LC3-II proteins could be observed with midazolam treatment, implying midazolam could induce autophagy to control MA-10 cell apoptosis. Furthermore, the expressions of p-EIF2α, ATF4, ATF3, and CHOP could be induced by midazolam, indicating that midazolam could stimulate apoptosis through ER stress in MA-10 cells. Additionally, the expressions of cyclin A, cyclin B, and CDK1 could be inhibited by midazolam, and the phosphorylation of p53, P27, and P21 could be adjusted by midazolam, suggesting that midazolam could manage cell cycle through the regulation of p53 pathway to induce apoptosis in MA-10 cells.ConclusionMidazolam could induce cell apoptosis through the activation of ER stress and the regulation of cell cycle through p53 pathway with the involvement of autophagy in MA-10 mouse Leydig tumor cells.

show abstract

Mechanisms Underlying Midazolam-Induced Peripheral Nerve Block and Neurotoxicity

Abstract: Our results indicate that processes underlying midazolam-induced nerve block and neurotoxicity are separable, and suggest that selective activation of TSPO may facilitate modality-selective nerve block while minimizing the potential for neurotoxicity.

Cited by 15 publications

References 23 publications

Neurotoxicity of common peripheral nerve block adjuvants

Neurotoxicity of common peripheral nerve block adjuvants

Dexmedetomidine versus midazolam for sedation during endoscopy: A meta-analysis

Midazolam regulated caspase pathway, endoplasmic reticulum stress, autophagy, and cell cycle to induce apoptosis in MA-10 mouse Leydig tumor cells

Contact Info

Product

Resources

About

Mechanisms Underlying Midazolam-Induced Peripheral Nerve Block and Neurotoxicity

Abstract: Our results indicate that processes underlying midazolam-induced nerve block and neurotoxicity are separable, and suggest that selective activation of TSPO may facilitate modality-selective nerve block while minimizing the potential for neurotoxicity.

Cited by 15 publications

References 23 publications

Neurotoxicity of common peripheral nerve block adjuvants

Neurotoxicity of common peripheral nerve block adjuvants

Dexmedetomidine versus midazolam for sedation during endoscopy: A meta-analysis

Midazolam regulated caspase pathway, endoplasmic reticulum stress, autophagy, and cell cycle to&nbsp;induce apoptosis in MA-10 mouse Leydig tumor cells

Contact Info

Product

Resources

About

Midazolam regulated caspase pathway, endoplasmic reticulum stress, autophagy, and cell cycle to induce apoptosis in MA-10 mouse Leydig tumor cells