GABA and central neuropathic pain following spinal cord injury

Spinal cord injury induces maladaptive synaptic transmission in the somatosensory system that results in chronic central neuropathic pain. Recent literature suggests that glial-neuronal interactions are important modulators in synaptic transmission following spinal cord injury. Neuronal hyperexcitability is one of the predominant phenomenon caused by maladaptive synaptic transmission via altered glial-neuronal interactions after spinal cord injury. In the somatosensory system, spinal inhibitory neurons counter balance the enhanced synaptic transmission from peripheral input. For a decade, the literature suggests that hypofunction of GABAergic inhibitory tone is an important factor in the enhanced synaptic transmission that often results in neuronal hyperexcitability in dorsal horn neurons following spinal cord injury. Neurons and glial cells synergistically control intracellular chloride ion gradients via modulation of chloride transporters, extracellular glutamate and GABA concentrations via uptake mechanisms. Thus, the intracellular “GABA-glutamate-glutamine cycle” is maintained for normal physiological homeostasis. However, hyperexcitable neurons and glial activation after spinal cord injury disrupts the balance of chloride ions, glutamate and GABA distribution in the spinal dorsal horn and results in chronic neuropathic pain. In this review, we address spinal cord injury induced mechanisms in hypofunction of GABAergic tone that results in chronic central neuropathic pain.This article is part of a Special Issue entitled ‘Synaptic Plasticity & Interneurons’.     

Pharmacological management of neuropathic pain following spinal cord injury

Spinal cord injury (SCI) has a number of severe and disabling consequences, including chronic pain, and around 40% of patients develop persistent neuropathic pain. Pain following SCI has a detrimental impact on the patient's quality of life and is a major specific healthcare problem in its own right. Thus far, there is no cure for the pain and oral pharmaceutical intervention is often inadequate, commonly resulting in a reduction of only 20-30% in pain intensity. Neuropathic pain sensations are characterized by spontaneous persistent pain and a range of abnormally evoked responses, e.g. allodynia (pain evoked by normally non-noxious stimuli) and hyperalgesia (an increased response to noxious stimuli). Neuropathic pain following SCI may be present at or below the level of injury. Oral pharmacological agents used in the treatment of neuropathic pain act either by depressing neuronal activity, by blocking sodium channels or inhibiting calcium channels, by increasing inhibition via GABA agonists, by serotonergic and noradrenergic reuptake inhibition, or by decreasing activation via glutamate receptor inhibition, especially by blocking the NMDA receptor. At present, only ten randomized, double-blind, controlled trials have been performed on oral drug treatment of pain after SCI, the results of most of which were negative. The studies included antidepressants (amitriptyline and trazodone), antiepileptics (gabapentin, pregabalin, lamotrigine and valproate) and mexiletine. Gabapentin, pregabalin and amitriptyline showed a significant reduction in neuropathic pain following SCI. Cannabinoids have been found to relieve other types of central pain, and serotonin noradrenaline reuptake inhibitors as well as opioids relieve peripheral neuropathic pain and may be used to treat patients with SCI pain.     

Antinociceptive effect of ambroxol in rats with neuropathic spinal cord injury pain

Symptoms of neuropathic spinal cord injury (SCI) pain include evoked cutaneous hypersensitivity and spontaneous pain, which can be present below the level of the injury. Adverse side-effects obtained with currently available analgesics complicate effective pain management in SCI patients. Voltage-gated Na⁺ channels expressed in primary afferent nociceptors have been identified to mediate persistent hyperexcitability in dorsal root ganglia (DRG) neurons, which in part underlies the symptoms of nerve injury-induced pain. Ambroxol has previously demonstrated antinociceptive effects in rat chronic pain models and has also shown to potently block Na⁺ channel current in DRG neurons. Ambroxol was tested in rats that underwent a mid-thoracic spinal cord compression injury. Injured rats demonstrated robust hind paw (below-level) heat and mechanical hypersensitivity. Orally administered ambroxol significantly attenuated below-level hypersensitivity at doses that did not affect performance on the rotarod test. Intrathecal injection of ambroxol did not ameliorate below-level hypersensitivity. The current data suggest that ambroxol could be effective for clinical neuropathic SCI pain. Furthermore, the data suggest that peripherally expressed Na⁺ channels could lend themselves as targets for the development of pharmacotherapies for SCI pain.     

阿米替林对神经病理性疼痛大鼠脊髓GLAST的影响

目的观察阿米替林对SNI大鼠脊髓谷氨酸-天冬氨酸转运体(GLAST)表达影响。方法60只♂SD大鼠,分为空白对照组(A)、SNI模型组(B)、阿米替林(AMI)注射对照组(C)、SNI模型+AMI治疗组(D),经腹腔分别给予0.2ml生理盐水(A、B)、10mg.kg-1AMI(C和D),每日两次。术后1、3、5d取各组大鼠L3~L6脊髓,分别检测GLAST的蛋白和mRNA表达改变,同时观察机械缩足反射阈值(mechanical withdrawal threshold,MWT)改变。结果与对照组相比,B组大鼠MWT随时间明显下降,GLAST蛋白和mRNA表达先增加再降低,C组大鼠MWT无改变,但是GLAST蛋白和mRNA表达随时间逐渐增加,D组大鼠MWT给药后3d停止下降,GLAST蛋白和mRNA表达明显增高,但不随时间变化。结论阿米替林可以增加GLAST蛋白表达,可能是治疗神经病理性疼痛的机制之一。     

Role of nitric oxide and reactive oxygen species in arthritis

A vast amount of circumstantial evidence implicates oxygen-derived free radicals, especially reactive oxygen species and nitric oxide as mediators of inflammation and/or tissue destruction in inflammatory and arthritic disorders. The aim of the current article is to overview the recent developments in this field, as it relates to the roles of nitric oxide (NO) and reactive oxygen species in the pathogenesis of this condition. The first part of the review focuses on the biochemical impact of NO and reactive oxygen species. The second part of the review deals with the novel findings related to the recently identified regulatory roles of the inducible isoform of nitric oxide synthase (iNOS) in the expression of pro-inflammatory mediators in inflammation. Reactive oxygen species can initiate a wide range of toxic oxidative reactions. These include initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3phosphate dehydrogenase, inhibition of membrane sodium/potassium ATP-ase activity, inactivation of membrane sodium channels, and other oxidative modifications of proteins. All these toxicities are likely to play a role in the pathophysiology of inflammation. Reactive oxygen species are all potential reactants capable of initiating DNA single strand breakage, with subsequent activation of the nuclear enzyme poly (ADP ribose) synthetase (PARS), leading to eventual severe energy depletion of the cells, and necrotic-type cell death. Recently it has been demonstrated that iNOS inhibitor prevents the activation of poly (ADP ribose) synthetase, and prevents the organ injury associated with inflammation. Although the severity and duration of inflammation may dictate the timing and extent of NOS expression, it is now evident that the up-regulation of NOS can take place during sustained inflammation. Thus, induced nitric oxide, in addition to being a "final common mediator" of inflammation, is essential for the up-regulation of the inflammatory response. Furthermore, a picture of a pathway is evolving that contributes to tissue damage both directly via the formation of reactive oxygen species, with them associated toxicities, and indirectly through the amplification of the inflammatory response.     

Role of reactive oxygen species in gallic acid-induced apoptosis

We earlier demonstrated that gallic acid (3,4,5-trihydroxybenzoic acid) induced apoptosis in promyelocytic leukemia HL-60RG cells, which was inhibited by catalase and intracellular Ca2+ chelator. In this study, we further studied the involvement of reactive oxygen species (ROS) and intracellular Ca2+ in gallic acid-induced apoptosis. The enhancement of intracellular ROS in HL-60RG cells was detected dose-dependently as early as 5 min after stimulation with gallic acid by using 5,6-carboxy-2',7'-dichlorofluorescin diacetate (DCFH-DA). Further studies that used various antioxidants and ROS scavengers showed that the intracellular peroxide level was well correlated with the potency to induce apoptosis and that the increased intracellular peroxides after gallic acid treatment seemed likely to result from the influx of H2O2 derived from superoxide which were generated extracellularly. In addition, gallic acid, HX/XO, and H2O2-induced apoptosis was completely inhibited by pretreatment with intracellular Ca2+ chelator 1,2-bis(2-aminophenoxyethane)-N,N,N'-tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA-AM), but increase of intracellular peroxide levels by gallic acid were suppressed only slightly. It is suggested that intracellular ROS induced by gallic acid plays an important role in eliciting an early signal in apoptosis. Especially, H2O, which is derived from superoxide anion generated extracellularly may increase intracellular Ca2+ levels or cooperate with intracellular Ca2+, thus resulting in apoptosis induction.     

白藜芦醇对急性脊髓损伤早期脂质过氧化反应和活性氧水平的抑制作用

目的 :探讨脊髓损伤后使用白藜芦醇 (resvera trol,Res)对脊髓损伤 (SCI)早期脂质过氧化反应和活性氧水平的抑制作用。方法 :采用重物下落撞击法制备成年大鼠的SCI模型 ,于损伤后即刻腹腔注射给予Res 5 0 ,1 0 0mg·kg-1和甲基强的松龙 (MPSS)1 0 0mg·kg-1,测定SCI后 1 ,2 4,48h时Res组受损脊髓组织超氧化物歧化酶 (SOD)和脂质过氧化反应产物丙二醛 (MDA)及活性氧 (ROS)水平 ,并与MPSS组进行疗效对比。结果 :Res 5 0mg·kg-1与 1 0 0mg·kg-1均能够显著提高SCI后损伤部位SOD水平和抑制MDA产生 (P <0 .0 1 ) ,以 48h为最明显 ;显著降低ROS水平 (P <0 .0 1 ) ,也以 48h最大 ,抑制率大于40 % ;且有明显剂量依赖性 ,作用与MPSS相当或更优。结论 :Res可以有效抑制脊髓损伤后早期受损局部脂质过氧化反应和活性氧水平 ,对脊髓损伤有潜在的保护与治疗作用     

Role of reactive oxygen species in the development of cytotoxicity with various forms of chewing tobacco and pan masala

The oral use of chewing tobacco has greatly increased in recent years, and this usage is associated with cancers of the mouth, lip, nasal cavities, esophagus and gut. Use of chewing tobacco is extremely popular in Far East and Middle East countries. In some of these countries, these chewing tobaccos are mixed with areca nut, lime and catechu and sold as pan masala. In this study, we examined three different forms of commercially available pan masala, and examined the development of cytotoxicity using primary culture of normal human oral keratinocytes (NHOKs). NHOK cells were treated with three different forms of pan masala, gutkha, pan masala with saccharin and pan masala as well as Kentucky smokeless chewing tobacco (STE) and the development of oxidative stress, and DNA damage were monitored. The results of our study demonstrated significant amount of the superoxide anion production, lipid peroxidation, DNA fragmentation and DNA ladders with all of the chewing tobacco materials tested. Laser scanning microscopy revealed concentration-dependent effects of STE on the modulation of intracellular redox states. The results, thus, document that the cytotoxic effects of the chewing tobaccos including pan masalas are mediated through the production of the reactive oxygen species.     

Role of reactive oxygen species in organophosphate insecticide phosalone toxicity in erythrocytes in vitro.

Reactive oxygen species (ROS) caused by organophosphates may be involved in the toxicity of various pesticides. Therefore, in this study we aimed to investigate how an organophosphate insecticide, phosalone, affects lipid peroxidation (LPO) and the antioxidant defence system in vitro. For this purpose, the effects of various doses of phosalone on LPO and the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) in erythrocytes were studied. Each phosalone dose was incubated with a previously prepared erythrocyte sample at +4 degrees C for 0, 60 and 180 min. After incubation, the levels of malondialdehyde (MDA) and the activities of SOD, GSH-Px and CAT were determined. Phosalone caused an increase in MDA formation and a decrease in the activities of SOD, GSH-Px and CAT. However, these effects were seen only at extremely high concentrations of phosalone and these concentrations were in the lethal range. Therefore, we suggest that ROS may not involve in the toxic effects of the pesticidal use of phosalone in low concentrations.     

己酮可可碱通过抑制小胶质细胞激活减轻大鼠痛觉超敏和痛觉过敏

目的:观察己酮可可碱腹腔注射对大鼠坐骨神经分支选择性损伤致神经病理性疼痛的作用.方法:切断腓总神经和胫神经保留腓肠神经,制作坐骨神经分支选择性损伤模型.16只雄性SD大鼠从术前1 d起至术后6 d腹腔注射己酮可可碱100 mg·kg-1,qd.观察术前1 d和术后1,3,5,7和14 d大鼠的机械缩足反射阈值(MWT)和热缩足反射持续时间(TWD);并测定不同组别脊髓小胶质细胞标志物0X-42的表达.实验同时设假手术组和坐骨神经分支选择性损伤模型组(n=16).结果:大鼠坐骨神经选择性切断后1 d起MWT降低、TWD延长,与假手术组比差异有显著性统计学意义(P<0.05);己酮可可碱组MWT增加、TWD缩短,与模型组相比差异有显著性统计学意义(P<0.05);己酮可可碱组部分坐骨神经切断后脊髓0X-42的表达和小胶质细胞阳性细胞数均显著减少.结论:己酮可可碱腹腔注射可抑制坐骨神经分支选择性损伤致脊髓小胶质细胞的激活,减轻痛觉超敏和痛觉过敏.     

Increase in hemokinin-1 mRNA in the spinal cord during the early phase of a neuropathic pain state

Background and purpose:

Substance P (SP), a representative member of the tachykinin family, is involved in nociception under physiological and pathological conditions. Recently, hemokinin-1 (HK-1) was identified as a new member of this family. Although HK-1 acts on NK₁ tachykinin receptors that are thought to be innate for SP, the roles of HK-1 in neuropathic pain are still unknown.

Experimental approach:

Using rats that had been subjected to chronic constrictive injury (CCI) of the sciatic nerve as a neuropathic pain model, we examined the changes in expression of SP- and HK-1-encoding genes (TAC1 and TAC4, respectively) in the L4/L5 spinal cord and L4/L5 dorsal root ganglia (DRGs) in association with changes in pain-related behaviours in this neuropathic pain state.

Key results:

The TAC4 mRNA level was increased on the ipsilateral side of the dorsal spinal cord, but not in DRGs, at day 3 after CCI. In contrast, the TAC1 mRNA level was significantly increased in the DRGs at day 3 after CCI without any changes in the dorsal spinal cord. Analysis of a cultured microglial cell line revealed the presence of TAC4 mRNA in microglial cells. Minocycline, an inhibitor of microglial activation, blocked the increased expression of TAC4 mRNA after CCI and inhibited the associated pain-related behaviours and microglial activation in the spinal cord.

Conclusions and implications:

The present results suggest that HK-1 expression is increased at least partly in activated microglial cells after nerve injury and is clearly involved in the early phase of neuropathic pain.     

Cannabinoid receptor-mediated antinociception with acetaminophen drug combinations in rats with neuropathic spinal cord injury pain

Pre-clinical evidence demonstrates that neuropathic spinal cord injury (SCI) pain is maintained by a number of neurobiological mechanisms, suggesting that treatments directed at several pain-related targets may be more advantageous compared to a treatment focused on a single target. The current study evaluated the efficacy of the non-opiate analgesic acetaminophen, which has several putative analgesic mechanisms, combined with analgesic drugs used to treat neuropathic pain in a rat model of below-level neuropathic SCI pain. Following an acute compression of the mid-thoracic spinal cord, rats exhibited robust hind paw hypersensitivity to innocuous mechanical stimulation. Fifty percent antinociceptive doses of gabapentin, morphine, tramadol or memantine were combined with an ineffective dose of acetaminophen; acetaminophen alone was not antinociceptive. The combination of acetaminophen with either tramadol or memantine resulted in an additive antinociceptive effect. Acetaminophen combined with either morphine or gabapentin, however, resulted in supra-additive (synergistic) efficacy. One of the analgesic mechanisms of acetaminophen is inhibiting the uptake of endocannabinoids from the extracellular space. Pre-treatment with AM251, a cannabinoid-1 receptor (CB1) antagonist, significantly diminished the antinociceptive effect of the acetaminophen + gabapentin combination. Pre-treatment with AM630, a cannabinoid-2 receptor (CB2) antagonist, did not have an effect on this combination. By contrast, both AM251 and AM630 reduced the efficacy of the acetaminophen + morphine combination. None of the active drugs alone were affected by either CB receptor antagonist. The results imply that modulation of the endocannabinoid system in addition to other mechanisms mediate the synergistic antinociceptive effects of acetaminophen combinations. Despite the presence of a cannabinoid mechanism, synergism was not present in all acetaminophen combinations. The combination of currently available drugs may be an appropriate option in ameliorating neuropathic SCI pain if single drug therapy is ineffective.     

Teratogenicity of the class III antiarrhythmic drug almokalant. Role of hypoxia and reactive oxygen species

The class III antiarrhythmic drug almokalant (ALM) was given to pregnant rats on Gestation Day 11 (125 micromol/kg) or 13 (25 micromol/kg). Other groups were pretreated with alpha-phenyl-N-t-butylnitrone, (PBN; 850 micromol/kg intraperitoneally) 1 h before administration of ALM or given (-)-2-oxo-4-thiazolidine carboxylic acid (OTC; 250 micromol/kg subcutaneously) 4 h before administration of ALM. PBN is a spin-trapping agent that can capture reactive oxygen species (ROS), and OTC is an antioxidant. Controls received tap water only. All groups (eight in total) consisted of 7 to 10 pregnant rats. ALM induced cardiovascular defects, orofacial clefts, and tail defects after administration on Day 11, and reduced the size of digits on Day 13. Pretreatment with PBN prevented induction of all the above-mentioned malformations by ALM. The results also indicated that OTC may have some protective effect against ALM-induced teratogenicity but not to the same extent as PBN. The results support the hypothesis that almokalant induces malformations via induction of episodes of embryonic arrhythmia/cardiac arrest, which result in hypoxia followed by reoxygenation and generation of ROS.     

活性氧在细菌耐抗生素机制中的作用

细菌对抗生素的耐药性以惊人的速度蔓延,阐明抗生素导致细菌死亡内在机制,对提高抗生素药效以及寻找新型抗生素显得尤为迫切。近期研究表明,抗生素引起的细菌内活性氧物质(reactive oxygen species,ROS)产生,是导致细菌细胞死亡的关键原因。该文对ROS、SOS和细菌耐药性方面的最新研究进行了综述和探讨,为开发新型抗菌药物,遏制细菌感染和耐药性提供新的思路。     

Role of cannabinoids in the management of neuropathic pain

The treatment of pain, particularly neuropathic pain, is one of the therapeutic applications of cannabis and cannabinoids that is currently under investigation and that stimulates interest among clinicians and basic researchers. Animal pain models, including models of acute, antinociceptive, inflammatory and neuropathic pain, have demonstrated the antinociceptive efficacy of cannabinoids without causing serious alterations in animal behaviour. These data, together with the historic and current empiric use of cannabinoids, support the interest in the analysis of their effectiveness in treating neuropathic pain. The evaluation of controlled trials that focus on the effect of cannabinoids on neuropathic pain reveals that this class of drugs is able to significantly reduce pain perception. Nevertheless, this effect is generally weak and clinical relevance remains under evaluation. Moreover, there is a lack of controlled trials and, in particular, comparisons with other drugs generally used in the treatment of neuropathic pain. Despite the fact that further research is required to achieve a definitive assessment, current data obtained from basic research and from analysis of the available controlled trials indicate that cannabinoids can be accepted as a useful option in the treatment of neuropathic pain.     

Ezetimibe and reactive oxygen species

Ezetimibe is a potent inhibitor of cholesterol absorption that has been approved for the treatment of hypercholesterolemia. Statin, 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is an inhibitor of cholesterol synthesis. Statin is the first-choice drug to reduce low-density lipoprotein (LDL)-cholesterol for patients with hypercholesterolemia, due to its strong effect to lower the circulating LDL-cholesterol levels. Because a high dose of statins causes concern about rhabdomyolysis, it is sometimes difficult to achieve the guideline-recommended levels of LDL-cholesterol in patients with high LDL-cholesterol treated with statin monotherapy. Ezetimibe has been reported to reduce LDL-cholesterol safely with both monotherapy and combination therapy with statins. Ezetimibe is especially expected to be the best pharmacological option for the treatment of patients unable to achieve LDL-cholesterol goals with statins. Reactive oxygen species (ROS) are produced at low levels to maintain physiological redox balance. Oxidative stress results when ROS production exceeds the ability of cells to detoxify ROS. Overproduction of ROS damages cellular components, including lipids, leading to decline in physiological function and cell death. Oxidative stress exacerbates atherosclerosis, the major risk factor for coronary artery disease and ischemic stroke, at every step involves the accumulation of oxidized LDL in the arteries, leading to foam cell formation, plaque development, and plaque rupture. This review focuses on the recent findings of ezetimibe-related atheroprotective effects in vasculature. Moreover, known and proposed mechanisms of how ezetimibe could improve ROS-induced pro-atherosclerotic conditions in vasculature are discussed; these effects may help to explain the mechanisms by which ezetimibe may protect vascular from atherosclerosis.     

Role of the dissolved zinc ion and reactive oxygen species in cytotoxicity of ZnO nanoparticles

With large-scale production and wide application of nanoscale ZnO, its health hazard has attracted extensive worldwide attention. In this study, cytotoxicity of different sized and shaped ZnO nanoparticles in mouse macrophage Ana-1 was investigated. And contribution of dissolved Zn(2+) and ROS in toxicity of ZnO particles was analyzed. The results indicated that ZnO particles manifested dose-dependent toxic effect on Ana-1 cells without size-dependence, and the particles shape may impact cytotoxicity of ZnO particles. When the concentration of dissolved Zn(2+) tended to equilibrium in the complete cell medium, the zinc ion concentration was approximately 10 μg/ml, inducing about 50% cell death, which was close to the cytotoxicity of ZnCl(2) (IC(50)=13.33 μg Zn/ml). The Zn(2+) concentration had significant correlations with cell viability and LDH level induced by the supernatant of ZnO particle suspensions (incubation at 37°C for 24h). Thus, the dissolved Zn(2+) played the main role in toxic effect of ZnO particles. Moreover, ROS generation assays demonstrated that ZnO particles produced intrinsically a small quantity of ROS, intracellular ROS was mainly produced after ZnO particles or the dissolved Zn(2+) entered into the cells. Although intracellular ROS had significant correlations with cell viability and LDH induced by ZnO particles, intracellular ROS may not be a major factor in cytotoxicity of ZnO nanoparticles, but the cytotoxic response.     

Response of glucose metabolism enzymes in an acute porphyria model. Role of reactive oxygen species

Acute hepatic porphyrias are human metabolic diseases characterized by the accumulation of heme precursors, such as 5-aminolevulinic acid (ALA). The administration of glucose can prevent the symptomatology of these diseases. The aim of this work was to study the relationship between glucose metabolism disturbances and the development of experimental acute hepatic porphyria, as well as the role of reactive oxygen species (ROS) through assays on hepatic key gluconeogenic and glycogenolytic enzymes; phosphoenolpyruvate carboxykinase (PEPCK) and glycogen phosphorylase (GP), respectively. Female Wistar rats were treated with three different doses of the porphyrinogenic drug 2-allyl-2-isopropylacetamide (AIA) and with a single dose of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Thus, rats were divided into the following groups: group L (100 mg AIA + 50 mg DDC/kg body wt.); group M (250 mg AIA + 50 mg DDC/kg body wt.) and group H (500 mg AIA + 50 mg DDC/kg body wt.). The control group (group C) only received vehicles (saline solution and corn oil). Acute hepatic porphyria markers ALA-synthase (ALA-S) and ferrochelatase, heme precursors ALA and porphobilinogen (PBG), and oxidative stress markers superoxide dismutase (SOD) and catalase (CAT) were also measured in hepatic tissue. On the other hand, hepatic cytosolic protein carbonyl content, lipid peroxidation and urinary chemiluminescence were determined as in vivo oxidative damage markers. All these parameters were studied in relation to the different doses of AIA/DDC. Results showed that enzymes were affected in a drug-dose-dependent way. PEPCK activity decreased about 30% in group H with respect to groups C and L, whereas GP activity decreased 53 and 38% in group H when compared to groups C and L, respectively. On the other hand, cytosolic protein carbonyl content increased three-fold in group H with respect to group C. A marked increase in urinary chemiluminescence and a definite increase in lipid peroxidation were also detected. The activity of liver antioxidant enzyme SOD showed an induction of about 235% in group H when compared to group C, whereas CAT activity diminished due to heme depletion caused by both drugs. Based on these results, we can speculate that the alterations observed in glucose metabolism enzymes could be partly related to the damage caused by ROS on their enzymatic protein structures, suggesting that they could be also linked to the beneficial role of glucose administration in acute hepatic porphyria cases.