Effects of Folinic Acid Administration on Lower Limb Ischemia/Reperfusion Injury in Rats.

Iñigo Cearra,Inmaculada Ruiz Montesinos,Diana Isabel Moreno-Franco,Ana Alonso-Varona,Ignacio García-Alonso,Borja Herrero De La Parte

doi:10.3390/antiox10121887

Abstract

Surgery under ischemic conditions, lasting up to 3 h, is routinely performed in orthopedic surgery, causing undesirable injury due to ischemia-reperfusion syndrome, with short and medium-term functional repercussions. To date, there is no established prophylactic treatment. In this work we evaluated folinic acid (FA) in a rodent model of lower limb ischemia-reperfusion (IRI-LL). 36 male WAG rats underwent 3 h of lower limb ischemia. In the saline group, rats received intraperitoneal administration of saline (used as vehicle for treatment). In the experimental group, rats were pretreated with FA (2.5 mg/kg) before the end of ischemia. After ischemia, animals were sacrificed at 3 h, 24 h or 14 days (for biochemical determination (Na+, K+, Cl-, urea, creatinine, CK, LDH, ALP, ALT, and AST), pathological assessment, or functional study using the rotarod test; respectively). Another six animals were used to establish the reference values. The prophylactic administration of FA significantly reduced the elevation of biochemical markers, especially those that most directly indicate muscle damage (CK and LDH). In addition, it also improved direct tissue damage, both in terms of edema, weight, PMN infiltrate and percentage of damaged fibers. Finally, the administration of FA allowed the animals to equal baseline values in the rotarod test; what did not occur in the saline group, where pre-ischemia levels were not recovered. Following 3 h of lower limb ischemia, FA minimizes the increase of CK and LDH, as well as local edema and leukocyte infiltration, allowing a faster recovery of limb functionality. Therefore, it could be considered as a prophylactic treatment when tourniquet is used in clinics.

Highlights

A common practice in extremity surgery, especially in orthopedic surgery, involves the application of controlled ischemia, commonly performed through the application of a pneumatic cuff as a tourniquet
Antioxidants 2021, 10, 1887 while making surgery easier, cause injury to the limb to which they are applied. This injury arises from the combination of three different factors: a) mechanical damage, due to the pressure of the pneumatic cuff on the tissues; b) anoxic damage, due to oxygen deprivation resulting from ischemia; c) inflammatory-oxidative damage, due to reperfusion when the pneumatic cuff is released
The latter two are intimately linked, and both may be grouped under the so-called ischemia-reperfusion injury (IRI), a phenomenon resulting from the reoxygenation of tissues previously subjected to anoxia

Summary

Introduction

A common practice in extremity surgery, especially in orthopedic surgery, involves the application of controlled ischemia, commonly performed through the application of a pneumatic cuff as a tourniquet This procedure provides a blood-free surgical field, which facilitates both anatomical dissection and identification of structures. Antioxidants 2021, 10, 1887 while making surgery easier, cause injury to the limb to which they are applied This injury arises from the combination of three different factors: a) mechanical damage, due to the pressure of the pneumatic cuff on the tissues; b) anoxic damage, due to oxygen deprivation resulting from ischemia; c) inflammatory-oxidative damage, due to reperfusion when the pneumatic cuff is released. The use of the ischemia cuff has been associated with a worse clinical recovery at least in the short and medium term (increased pain, edema, quadriceps weakness...) [3,4,5,6,7,8], which has even led some authors to question the risk-benefit balance of using the ischemia cuff in knee arthroplasty [9]

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Conclusion