Metformin as an alternative therapeutic intervention in hemorrhagic shock

Abstract

Hemorrhagic shock (HS) continues to significantly contribute to civilian and military mortality, underscoring the critical need for new resuscitation strategies. Recent discussions have emphasized the pivotal role of impaired oxygen delivery and cellular metabolism in exacerbating HS-related damage. Metformin, a well-established diabetes medication, exhibits promising potential to enhance cellular metabolism and activate pathways linked to improved oxygen uptake, thereby optimizing cellular energy management. Thus, this study aimed to assess metformin's effcacy in ameliorating outcomes in animals subjected to HS. To achieve this, Wistar rats were surgically prepared with femoral artery and vein catheters. HS was induced by controlled blood withdrawal to maintain a mean arterial pressure (MAP) within the range of 35-40 mmHg for 90 minutes. Throughout the protocol, blood pressure (BP) and heart rate (HR) were assessed. The animals were divided into two groups: Lactated Ringer's solution (LR) and LR treated with Metformin (Met). Metformin was administered in three bolus injections: at the start of resuscitation (10mg), 45 minutes into resuscitation (5mg), and 90 minutes into resuscitation (5mg). After 120 minutes, the animals were euthanized, and blood samples were collected for subsequent analysis, including metabolomic profiling of the tricarboxylic acid (TCA) cycle, amino acids, and lipids. Additionally, trypsin-like enzyme activity in the plasma and markers of brain injury were evaluated. Animals treated with Met showed significantly higher systolic blood pressure after resuscitation (LR: 74±5 mmHg vs. LR+Met: 94±3 mmHg) with no significant changes in HR observed. Brain injury markers such as GFAP (Glial fibrillary acidic protein), S100B (astrocytic protein specific to the central nervous system), Tau (microtubule-associated protein), and NFL (axonal protein neurofilament light) were assessed. Animals reperfused with LR and treated with Met displayed a 22% reduction in GFAP levels compared to those reperfused with LR alone, while other markers remained unchanged. Met treatment also led to a reduction in plasmatic metabolites, including Lactate (30%), Succinate (24%), and Fumarate (22%), along with an increase in Citrate (23%) and α-ketoglutarate (24%)—all constituents of the TCA cycle. Additionally, an increase in amino acid metabolites and a decrease in lipid metabolites were observed. Recent research has suggested that HS results in elevated levels of trypsin-like enzymes in the plasma and that inhibiting these enzymes might improve outcomes during resuscitation. Our study revealed that treatment with Met reduced approximately 60% of trypsin-like enzyme activity in the plasma compared to the LR-only group. In conclusion, our study demonstrates that Met, when administered in conjunction with LR as a resuscitation solution, significantly enhances post-resuscitation BP compared to LR alone. This improved outcome may be associated with alterations in the TCA cycle and the inhibition of trypsin-like enzyme activity. However, further investigations are necessary to elucidate the precise role of these changes in the observed enhancements within this experimental model. This work was supported by National Institutes of Health grant R01HL162120. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.