Increased Serum Creatine Phosphokinase Activity Research Articles

Acetamiprid induces cardiotoxicity in rats by dysregulating α7 nAChR and its downstream targets: The ameliorative role of resveratrol

Acetamiprid (ACP) is a novel neonicotinoid insecticide used for controlling insect pests. Resveratrol (RSV) is a natural polyphenol that possesses anti-oxidant, anti-inflammatory and anti-apoptotic actions. The current research explores the mechanism of ACP-induced cardiotoxicity and the alleviative effects of RSV. Male rats were allocated to four groups of ten each. Rats were treated daily for 90 days via oral route. Control rats received distilled water, ACP rats received 25 mg acetamiprid/kg, RSV rats received 20 mg resveratrol/kg and ACP + RSV rats received both ACP and RSV. ACP exposure increased serum creatine phosphokinase activity and cardiac troponin level. It also induced oxidative stress, as evidenced by the glutathione reduction, and malondialdehyde elevation, as well as the detrimental histopathological and immunohistochemical changes in the myocardium. Gene expression analysis revealed down-regulation in the mRNA expression of the survival-related genes α7 nAChR, Erk and Bcl-2, and up-regulation in the apoptosis-related genes Jnk, Bax and Caspase-3. Conversely, the concomitant administration of ACP with RSV alleviated most of the aforementioned toxic impacts. It can be concluded that ACP induces cardiotoxicity by dysregulating the mRNA expression of α7 nAChR and its downstream targets. Additionally, RSV is proved to be a promising ameliorative agent against ACP-induced cardiotoxicity.

Dietary fish oil and vitamin E enhance doxorubicin effects in P388 tumor-bearing mice.

In this study, four kinds of rodent diets, CO, FO, CVe, and FVe, were used by addition of canola oil, oil mixture (fish oil + canola oil), canola oil plus vitamin E, and oil mixture plus vitamin E, respectively, to a basic diet, AIN-93G, to investigate the influence of dietary fish oil and vitamin E on doxorubicin (DOX) treatment in P388 ascitic mice. Animal life span (LS) and heart damage were recorded in mice fed the four different diets and treated with different doses of DOX. The optimal doses of DOX for antitumor effect as manifested by increased LS were 6.0 and 9.0 mg/kg. Both fish oil and vitamin E significantly enhanced this effect. On the other hand, DOX at 12.0 mg/kg induced severe heart damage, which was also significantly aggravated by both fish oil and vitamin E, as shown by both decreased LS and increased serum creatine phosphokinase activity. Fish oil and vitamin E appeared to enhance the antitumor effect of optimal doses of DOX but to aggravate cardiotoxicity owing to DOX overdose.

Antibodies against intercellular adhesion molecule 1 protect against myocardial ischaemia-reperfusion injury in rat

In this study we have assayed the pathophysiological role of intercellular adhesion molecule (ICAM-1), a cytokine-inducible adhesion molecule, in a model of ischaemia reperfusion in the rat. Anaesthetized rats were subjected to occlusion (1 h) of the left main coronary artery followed by reperfusion (1 h). Sham myocardial ischaemia-reperfusion rats (Sham MI/R) were used as controls. Myocardial ischaemia plus reperfusion in untreated rats decreased survival rate, produced a marked myocardial necrosis, increased serum creatine phosphokinase activity, and cardiac myeloperoxidase activity (a marker enzyme commonly used to assess polymorphonuclear leukocyte accumulation). Furthermore, rats subjected to myocardial ischaemia-reperfusion showed an increased pressure rate index, studied as a quantitative means for assessing myocardial oxygen demand. Treatment with monoclonal anti-rat ICAM-1 (1 mg/kg i.v.), 3 h before occlusion of the left main coronary artery, significantly lowered serum creatine phosphokinase activity, blunted leukocyte accumulation and protected the myocardium from injury subsequent to ischaemia and reperfusion injury. These investigations have revealed that ICAM-1 is a critical adhesion molecule in the pathogenesis of ischaemia-reperfusion injury. In addition these results suggest that the use of monoclonal antibodies raised against ICAM-1 can represent a useful tool for the prevention of ischaemia-reperfusion damage.

E-selectin in the pathogenesis of experimental myocardial ischemia-reperfusion injury

The role of E-selectin in the pathogenesis of an experimental model of myocardial ischemia-reperfusion injury was investigated. Pentobarbital anesthetized rats underwent left main coronary artery ligation (1 h) followed by reperfusion (1 h; MI/R). Sham operated rats were used as controls (sham MI/R). Myocardial ischemia-reperfusion injury reduced survival rate (50%), caused severe myocardial damage (necrotic area/area-at-risk 69.8 ± 5%; necrotic area/total=area = 56 ± 7.6%), increased serum creatine phosphokinase activity (sham MI/R = 33 ± 3 U/ml; MI/R = 215 ± 13 U/ml) and elevated myeloperoxidase activity (investigated as an index of leukocyte adhesion and accumulation; sham MI/R = 0.11 ± 0.02 U × 10 −3/g tissue) in the area-at-risk (7.5 ± 1.7 U × 10 −3/g tissue) and in the necrotic area (7.8 ± 2.2 U × 10 −3/g tissue). Furthermore, MI/R rats had an increased pressure rate index, studied as a quantitative means for assessing myocardial oxygen demand. Administration of a hyperimmune serum containing antibodies against E-selectin significantly improved survival rate (80%), reduced myocardial injury (necrotic area/area-at-risk = 26.4 ± 7%, P < 0.005; necrotic area/total area 19.1 ± 2.8%, P < 0.005), lowered serum creatine phospokinase activity (85 ± 5 U/ml, P < 0.001) and decreased myeloperoxidase actibity in the area at risk (3.7 ± 1.3 U × 10 −3/g tissue, P < 0.001) and in the necrotic area (3.0 ± 0.7 U × 10 −3/g tissue). Finally, the administration of anti E-selection antibodies improved the PRI in MI/R rats. The present data suggest that E-selectin in vivo plays a key role in the pathogenesis of myocardial ischemia/reperfusion injury.

Reduction of myocardial leukocyte accumulation and myocardial infarct size following administration of BAY u3405, a thromboxane A2 receptor antagonist, in myocardial ischaemia-reperfusion injury

We investigated the effect of BAY u3405, a thromboxane A2 receptor antagonist in pentobarbital anaesthetized rats subjected to left main coronary artery ligation (1 h) followed by reperfusion (1 h; MI/R). Sham operated rats were used as controls (Sham MI/R). Survival rate, myocardial necrosis, myocardial myeloperoxidase activity (investigated as an index of leukocyte adhesion and accumulation) and serum creatine phosphokinase activity were studied. Ischaemia-reperfusion injury significantly reduced the survival rate (45%), caused a marked myocardial necrosis, increased serum creatine phosphokinase activity (Sham MI/R = 26 +/- 10.2 U/ml; MI/R = 213 +/- 19 U/ml) and produced a rise in myocardial myeloperoxidase activity in the area-at-risk and in the necrotic area (6.1 +/- 0.4 U x 10(-3)/g tissue and 6.7 +/- 0.9 U x 10(-3)/g of tissue, respectively). The administration of BAY u3405 (30 and 60 mg/kg/i.v., 30 min before occlusion) significantly increased survival rate, lowered the area of myocardial necrosis, blunted the increase in serum creatine phosphokinase activity and reduced the increase in myeloperoxidase activity in both the area-at-risk and the necrotic area. Furthermore, the protective effect of BAY u3405 was dose-dependent. These data are consistent with an involvement of TXA2 in myocardial ischaemia-reperfusion injury and suggest that BAY u3405 may represent a novel therapeutic approach to the treatment of acute ischaemia-reperfusion injury.

G619, a dual thromboxane synthase inhibitor and thromboxane A2 receptor antagonist, reduces myocardial damage and polymorphonuclear leukocyte accumulation following coronary artery occlusion and reperfusion in rats.

We investigated the effect of G 619, a dual thromboxane synthase inhibitor and thromboxane A2 (TxA2) receptor antagonist, in pentobarbital-anaesthetized rats subjected to left main coronary artery ligation (1 h) followed by reperfusion (1 h; MI/R). Sham-operated rats were used as controls (sham MI/R). Survival rate, myocardial necrosis, myocardial myeloperoxidase (MPO) activity (investigated as an index of leukocyte adhesion and accumulation) and serum creatine phosphokinase (CPK) activity were studied. MI/R injury significantly reduced survival rate (45%), caused a marked myocardial necrosis, increased serum CPK activity (sham MI/R = 35 +/- 12 U/ml; MI/R = 205 +/- 13 U/ml) and produced an increase in myocardial MPO activity in the area at risk and in the necrotic area (6.3 +/- 0.5 and 6.6 +/- 0.9 U x 10(-3)/g tissue, respectively). The administration of G 619 significantly increased survival rate, lowered the area of necrosis, blunted the increase in serum CPK activity and reduced the increase in MPO activity in both the area at risk and the necrotic area. These data are consistent with an involvement of TxA2 in MI/R injury and suggest that G 619 may represent a novel therapeutic approach to the treatment of acute myocardial infarction.

Comparative study of three phospholipase A 2s from the venom of Vipera aspis

1. 1. Three phospholipase A 2s, PLA 2-I, PLA 2-II and PLA 2-III, were isolated from Vipera aspis venom by gel filtration and ion exchange chromatography. 2. 2. Purified PLA 2-I, -II and -III have mol. wts of 30,200, 16,000 and 13,500, and isoelectric points of 9.45, 7.65 and <4.1, respectively. 3. 3. PLA 2-I consists of an acidic subunit (mol. wt 13,700, pI: <3.5) and a basic subunit (mol. wt 16,500, pI: 10.6), which can be separated under highly acidic conditions. 4. 4. PLA 2-I possessed lethal activity and LD 50 for this preparation was estimated to be 0.288 (0.209–0.397) μg/g, while lethality was not observed when PLA 2-II, -III or each subunit of PLA 2-I were administered. 5. 5. Capillary permeability-increasing activity was found in the samples which possessed basic isoelectric points. Additionally, PLA 2-I and its basic subunit drastically prolonged activated partial thromboplastin time of platelet rich plasma. 6. 6. Intramuscular injections of PLA 2-I, -II and -III increased serum creatine phosphokinase activity in mice, indicating that damage in muscle was caused by these enzymes. 7. 7. NH 2-terminal sequences of the three PLA 2-s were compared with other phospholipase A 2s from snake venoms. Furthermore, antigenicities were tested using antiserum prepared against each sample.

Autosomal recessive inherited phosphofructokinase deficiency in English springer spaniel dogs

Three families of English springer spaniel dogs with phosphofructokinase (PFK) deficiency causing haemolysis were studied. Four male dogs and one female dog with chronic haemolysis and haemolytic crises were found to have markedly reduced PFK activity in erythrocytes (8-20% of control English springer spaniels). PFK-deficient erythrocytes exhibited an extreme alkaline and sucrose lysis. The oxygen dissociation curve of erythrocyte suspensions was shifted to the left with a 50% saturation of haemoglobin at a partial oxygen pressure of 16-17 mmHg (normal 26-31 mmHg). Muscle wasting and mildly increased serum creatine phosphokinase activity were also noted. Six clinically normal first degree relatives of affected dogs had erythrocyte PFK activities that were 38-51% of controls. In these family members, there was an erythrocytosis and mild reticulocytosis probably due to a mildly enhanced haemoglobin-oxygen affinity but no increase in serum creatine phosphokinase. These studies confirm the familial nature of muscle-type PFK deficiency in English springer spaniels and support the conclusion that this animal model of the human glycogen storage disease type VII is inherited as an autosomal recessive trait.

Serum pyruvate-kinase (PK) and creatine-phosphokinase (CPK) in female relatives and patients with X-linked muscular dystrophies (Duchenne and Becker)

Determination of serum creatine phosphokinase (CPK) activity is often used in efforts to detect carriers of X-linked muscular dystrophies. We have recently demonstrated that another serum enzyme, pyruvate-kinase (PK) may also be of use in the diagnosis of patients affected with a variety of neuromuscular disorders. To evaluate the usefulness of this assay for carrier detection, a comparative study of serum PK and CPK activity was performed in 74 female relatives of patients affected with Duchenne (DMD) and Becker (BMD) muscular dystrophies. For obligate carriers of the DMD gene, 10 of 14 had elevated CPK's, 11 of 14 had elevated PK's and 12 of 14 had abnormal results for either of the two enzymes. Three of 16 mothers of isolated cases had increased serum CPK activity and 6 of 16 had increased PK activity (7 had elevation of at least one enzyme). These preliminary data suggest that the use of PK may enhance the capability to discriminate carriers for these X-linked recessive genes.

Serum creatine phosphokinase activity in asthma.

Serum creatine phosphokinase activity was measured in 2 groups of asthmatics. The first group consisted of 12 asthmatics followed as outpatients for periods of up to 16 months. Serum creatine phosphokinase activity increased in 8 patients and correlated with the severity of subjective symptoms and objective measurement of airway obstruction, as represented by the forced expiratory volume in 1 second. In the second group, consisting of 5 asthmatic patients studied during hospitalization for acute exacerbations of asthma, serum creatine phosphokinase activity was increased on admission in all the patients and decreased as symptoms and airway obstruction improved and alveolar ventilation decreased. Analysis of creatine phosphokinase isoenzymes showed the increase in every instance to be due entirely to skeletal muscle isoenzyme. The results of additional laboratory tests and further evaluation suggested that the increased serum creatine phosphokinase activity was not derived from the myocardium and was not related to parenteral therapy, specific drugs, hyperthermia, or hyperkalemia. The increase in serum creatine phosphokinase during exacerbations of asthma is probably derived from respiratory muscles, owing to the increased work of breathing.

Histochemistry of creatine phosphokinase

In a preliminary experiment, brief formaldehyde fixation of rat myocardium permitted preservation of creatine phosphokinase (CPK) activity and fine structure. Electrophoresis of the homogenate of the fresh and fixed myocardium demonstrated mitochondrial and three non-mitochondrial CPK isoenzymes. An osmiophilic tetrazolium salt and ferricyanide were used for the electron microscopic demonstration of CPK. With tetrazolium, the reaction products were localized near the inner mitochondrial membrane in the intermembranous space of mitochondria, but the reaction was noted on the matrix side of the membranes with ferricyanide. Reaction was also present in the sarcoplasmic reticulum (SR) of the skeletal muscle. Both heart and skeletal muscle showed diffuse background cytoplasmic reaction. The heat-sensitive brain-type isoenzyme of CPK was present in the extramitochondrial sarcoplasm of the heart muscle. CPK activity was demonstrated in isolated heart mitochondria and skeletal muscle SR. Myocardial degeneration was produced in the rat myocardium by injection of isoproterenol. Two to 4 h after the injection there was an extensive histochemical reduction of CPK activity in the myocardium. Twelve to 24 h after injection, most of the areas with initially reduced CPK reaction recovered the enzyme activity and only the subendocardial layer underwent necrosis without recovery of the CPK activity. The maximal rate of increase in serum CPK activity coincided with the most extensive depletion of the myocardium CPK. Mitochondrial isoenzyme did contribute to elevation of serum CPK and appeared to remain in the injured myocardial cells.

Serum creatine phosphokinase activity in psychiatrically hospitalized children.

Serum creatine phosphokinase (CPK) activity was determined in a series of 101 sequential admissions to the Pritzker Children's Hospital, an inpatient psychiatric facility. Black children had significantly higher serum CPK levels than whites, and males had significantly higher levels than females, as is the case with adults. There was a higher incidence of CPK elevations in children with organic brain pathology than in children with personality disorders or schizoprenia. Children with chronic symptoms of a psychotic nature did not have increased serum CPK activity, which is similar to the findings in adults. There were no children in the sample with acute psychotic symptoms, so it was not possible to determine whether acute psychosis in children is accompanied by increased serum CPK activity, as it frequently is in psychotics over the age of 17.

Serum creatine phosphokinase (CPK) activity in monozygotic twins discordant for schizophrenia: Heritability of serum CPK activity

Recent studies with normal monozygotic and dizygotic twins have established that serum creatine phosphokinase (CPK) activity in man is under genetic control (Meltzer, Dorus, and Davis, in preparation). This is of interest because of the reports that serum CPK activity is increased in many acutely psychotic patients, provided that they are studied in the first days after the onset of gross psychotic symptoms and throughout hospitalization. 1–12 The increases range from slightly above the 95% upper limits of normal to 50–75 times the limits for each race-sex group. Furthermore, 25%–30% of the first degree relatives of psychotic patients have slight but persistent increases in serum CPK activity. 2,3,7 These increases occur significantly more frequently in relatives of psychotic patients who have themselves had increases in serum CPK activity (Meltzer and Moretti, in preparation). Prior to the studies with normal twins which established that serum CPK activity is under some genetic control, we had the opportunity to study serum CPK activity in twins discordant for schizophrenia. These results will be reported here.

Serum creatine phosphokinase in normal newborns.

Serum creatine phosphokinase (CPK) activity in 70 normal newborns was found to be significantly higher than the normal values found in adults or older children, and in some cases reached a level up to 10 times normal. It declined to near normal activity during the first 4 days and to normal level of activity by age 6-10 weeks. No clear correlation between birth trauma and increase in serum CPK activity was shown. CPK activity in cord blood was lower than in venous and capillary blood. Because of the increased CPK activity found in normal newborns, screening for Duchenne-type muscular dystrophy should be postponed for a few weeks after delivery.

Plasma creatine phosphokinase levels in rats following lysergic acid diethylamide.

Lysergic acid diethylamide (LSD) injected intraperitoneally or intramuscularly did not increase rat plasma creatine phosphokinase (CPK) activity. LSD did not produce an increase in serum CPK activity in rats kept in a 2 degrees C environment for 2 hrs. LSD also did not potentiate, in rats, the increase in plasma CPK activity produced by restraint at 2 degrees C or 24 degrees C. It is likely that the increases in serum CPK activity previously reported to occur in people who became psychotic following LSD ingestion are a consequence of the psychotic state itself rather than a direct effect of LSD.

Subterminal motor nerve abnormalities in psychotic patients.

THERE is considerable evidence of neuromuscular dysfunction in most patients with all types of the functional psychoses. Examples of such dysfunction are (1) increased activity of skeletal-muscle-type creatine phosphokinase (CPK) in serum in the acute stage of psychosis1–4; (2) abnormally large increases in serum CPK activity with a standardised exercise test performed by patients in symptomatic remission5; (3) morphological abnormalities in skeletal muscle fibres at biopsy, particularly scattered atrophic fibres and extensive areas of Z-band streaming6–8; and (4) abnormalities of eye movements in tracking a pendulum9. The skeletal muscle fibre abnormalities found in psychotic patients are likely to be neurogenic in origin10.

Psychomotor activity and serum creatine phosphokinase activity.

An investigation of the relationship between psychomotor activity and serum creatine phosphokinase (CPK) activity showed significant positive correlations regardless of the serum CPK activity. The highest positive correlations were found between preceding evening and nocturnal activity and serum CPK activity, especially in acute schizophrenia, borderline states, and manic-depressive disease. While this finding may reflect the negative correlations between sleep time and serum CPK activity, it is also consistent with the hypothesis that postexercise CPK activity peaks occur approximately eight hours after exercise. Increases in serum CPK activity may also occur subsequent to disordered phasing of psychomotor activity peaks and corticosteroid levels affecting the membrane permeability in skeletal muscle.

Increased serum creatine phosphokinase activity with violent coughing.

Increased serum creatine phosphokinase activity with violent coughing.

Rigidity, hyperpyrexia and coma following fluphenazine enanthate.

Beginning one day after receiving fluphenazine enanthate (Prolixin Enanthate®), 25 mg, subcutaneously, an acute schizophrenic girl with mixed schizoaffective and excited catatonic symptomatology became mute and withdrawn, then developed severe muscular rigidity and hyperpyrexia, and finally became comatose. The patient developed large increases in serum creatine phosphokinase (CPK) activity by the third day of this syndrome. The previously described symptoms, which have been labeled the neuroloptic “malignant” syndrome (Delay and Deniker, 1968), diminished with supportive treatment and intravenous benztropine mesylate (Cogentin®). Because of renewed psychotic behavior, phenothiazine treatment was eventually restarted, including treatment with fluphenazine enanthate, without recurrence of the extrapyramidal or hypothalamic symptoms. The difficulty in distinguishing between the neuroleptic “malignant” syndrome and Stauder's “acute lethal catatonia” is emphasized. The relationship between these syndromes and malignant hyperpyrexia is discussed. Possible causes of the increased serum CPK activity are discussed.

Ethanol produces muscle damage in human volunteers.

Repeated administration of ethanol (42 percent of total calories) for 28 days increased serum creatine phosphokinase activity and produced ultrastructural changes in skeletal muscle of human volunteers. The data suggest that alcoholic myopathy results from ethanol toxicity, rather than from nutritional or other factors.