Skeletal Muscular Strength Research Articles

Fermented Whey Protein Supplementation Improves Muscular Strength, Muscle Parameters, and Physical Performance in Middle-Aged Korean Adults: An 8-Week Double Blind Randomized Controlled Trial.

The present study evaluated the effects of fermented whey protein using kimchi lactic acid bacteria Lactobacillus casei DK211 on skeletal muscle mass, muscle strength, and physical performance in healthy middle-aged males performing regular resistance exercises. Effective protein supplementation and regular exercise are two important factors for improving muscle health. Therefore, in this study, the effects of consuming fermented whey protein twice a day were investigated and compared with that of non-fermented supplementation. Forty-eight males (average age 44.8) were randomly assigned to two groups: Fermented whey protein supplementation (FWPS) and non-fermented whey protein concentration supplementation (WPCS) groups. Each group ingested 37 g of FWPS or WPCS twice a day for eight weeks. Body composition, muscle strength, and physical performance were assessed pre- and post-intervention. Independent t-tests or chi-square tests for the categorical variables were performed for analyzing the observations. FWPS was effective in promoting the physical performance in dynamic balance measurement and muscle health, indicated through the increment in grip strength (left), upper arm circumference, and flat leg circumference from the baseline. However, similar improvements were not observed in the WPCS group. These results imply that whey protein fermented by L. casei DK211 is an effective protein supplement for enhancing muscle health in males performing regular resistance exercises.

ASSOCIATION BETWEEN SPORT RELATED POLYGENIC PROFILE AND MAGNITUDE OF PHYSICAL PERFORMANCES CHANGES FOLLOWING RESISTANCE TRAINING AMONG NOVICE FIELD HOCKEY ATHLETES

Background: Studies have shown that inter-individual variation in response to resistance training is attributed to genetic variation. Aim: To correlate total genotype scores (TGS) with the magnitude of physical performances (skeletal muscle mass, muscular strength, muscular power, performance decrement, and VO2max) change, following 8 weeks of resistance training. Methods: We included forty-five (N=45) participants (age = 16.53 ± .5 years old, body mass = 61.03 ± 6.67 kg, height = 1.67±.05 m) and randomly assigned into; high intensity resistance training (n=15), moderate intensity resistance training (n=15) and a control group (n=15). They were prescribed with the same upper and lower body exercise routines. Pre- and post-test physical performances were measured. Genotyping was conducted using in-house designed allele-specific polymerase chain reaction assays. TGS for nine SNPs: Angiotensin Converting Enzyme, ACE rs1799752; Alpha-acitin-3, ACTN3 rs1815739; Adrenergic Receptor B3, ADRB3 rs4994; Angiotensinogen, AGT rs699; Bradykinin Receptor B2, BDKRB2 rs1799722; Peroxisome Proliferator-Activated Receptor Alpha, PPARA rs4253778; Peroxisome Proliferator-Activated Receptor Gamma Co-Activator 1-Alpha, PPARGC1A rs8192678; Thyrotropin Releasing Hormone Receptor, TRHR rs7832552 and Vascular Endothelial Growth Factor, VEGF rs1870377,were calculated and assigned with strength-power and endurance quality. Pearson correlation analysis was employed to investigate the correlation between TGS, and magnitude of physical performances change following intervention. Result: There is a significant correlation between strength-power TGS with lower body muscular strength (r= .65, p<.01) and power (r= -.69, p<.01) following moderate intensity resistance training. Conclusion: In this study, it is demonstrated that participants with higher strength-power TGS, gained greater lower body strength improvement and lesser muscular power decrement even with moderate intensity as compared to high intensity resistance training. Therefore, personalising training based on athlete’s genetic profile may optimise performance.

Resistin as a Systemic Inflammation-Related Biomarker for Sarcopenia in Patients With Chronic Obstructive Pulmonary Disease.

BackgroundSarcopenia is common in patients with chronic obstructive pulmonary disease (COPD) and is mainly caused by systemic inflammation. Resistin acts as a proinflammatory cytokine and is involved in the activation of multiple inflammatory signaling pathways. The aim of this study was to determine the relationship between resistin levels and systemic inflammation and to assess the clinical value of circulating resistin for sarcopenia in patients with COPD.MethodsIn this prospective observational study, we enrolled 235 patients with COPD who were divided into development and validation sets. The definition of sarcopenia followed the guidelines from the Asian Working Group for Sarcopenia. Serum concentrations of resistin and TNF-α were measured using an enzyme-linked immunosorbent assay (ELISA).ResultsIn this study, higher serum resistin levels were significantly associated with lower skeletal muscle mass and muscular strength. The serum resistin levels in patients with sarcopenia were significantly higher than those in patients without sarcopenia. The serum resistin level had positive correlations with the serum TNF-α level (r = 0.250, p = 0.007). The predictive efficacy of the serum resistin level (AUC: 0.828) for sarcopenia was superior to that of the serum TNF-α level (AUC: 0.621). The cutoff point (7.138 ng/ml) for the serum resistin level was validated in the validation set (AUC: 0.818).ConclusionsSerum resistin levels were associated with systemic inflammation and can be used accurately and easily to predict sarcopenia in patients with COPD.

Influence of Umbelliferone on the Anticonvulsant and Neuroprotective Activity of Selected Antiepileptic Drugs: An In Vivo and In Vitro Study.

Umbelliferone (7-hydroxycoumarin; UMB) is a coumarin with many biological properties, including antiepileptic activity. This study evaluated the effect of UMB on the ability of classical and novel antiepileptic drugs (e.g., lacosamide (LCM), levetiracetam (LEV), phenobarbital (PB) and valproate (VPA)) to prevent seizures evoked by the 6-Hz corneal-stimulation-induced seizure model. The study also evaluated the influence of this coumarin on the neuroprotective properties of these drugs in two in vitro models of neurodegeneration, including trophic stress and excitotoxicity. The results indicate that UMB (100 mg/kg, i.p.) significantly enhanced the anticonvulsant action of PB (p < 0.01) and VPA (p < 0.05), but not that of LCM orLEV, in the 6-Hz test. Whether alone or in combination with other anticonvulsant drugs (at their ED50 values from the 6-Hz test), UMB (100 mg/kg) did not affect motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength; or passive avoidance tests, respectively. Pharmacokinetic characterization revealed that UMB had no impact on total brain concentrations of PB or VPA in mice. The in vitro study indicated that UMB has neuroprotective properties. Administration of UMB (1 µg/mL), together with antiepileptic drugs, mitigated their negative impact on neuronal viability. Under trophic stress (serum deprivation) conditions, UMB enhanced the neurotrophic abilities of all the drugs used. Moreover, this coumarin statistically enhanced the neuroprotective effects of PB (p < 0.05) and VPA (p < 0.001) in the excitotoxicity model of neurodegeneration. The obtained results clearly indicate a positive effect of UMB on the anticonvulsant and neuroprotective properties of the selected drugs.

Design, synthesis and evaluation of piperazine clubbed 1,2,4-triazine derivatives as potent anticonvulsant agents

The new series of N-(5,6-diphenyl-1,2,4-triazin-3-yl)-2-(4-substituted piperazin-1-yl) acetamide (RP1–5) and 2-((5,6-diphenyl-1,2,4-triazin-3-yl)thio)-1-(4- substituted piperazin-1-yl)-ethan-1-one (RP6–10) derivatives were designed and synthesised by clubbing substituted 5,6-diphenyl-1,2,4-triazine with different substituted piperazines. The synthesized compounds were tested for anticonvulsant activity and various biochemical toxicity parameters. Among the series, two compounds (2-(4-benzylpiperazin-1-yl)-N-(5,6-diphenyl-1,2,4-triazin-3-yl)acetamide (RP4), and 2‑chloro-1-(4-substituted piperazin-1-yl)ethan-1-one (RP5) were found to demonstrate the most potent anticonvulsant activity in both MES and scPTZ convulsion mice models. The most active compound RP5 was effective at median doses (ED50) of 14.82 mg/kg in MES and 14.61 mg/kg in scPTZ model. The median toxic dose (TD50) was > 600 which provided the compound RP5 with high protective index of 40.48 in the MES test and 41.06 in scPTZ test. Further, both the compounds were also found to possess significant antidepressant activity. The compounds did not show any adverse effect in various parameters such as grip-strength test (skeletal muscular strength), actophotometer, and rotarod test (locomotor) as compared to the control groups. In biochemical estimation, RP4 and RP5 were found nontoxic and showed no sign of any pathological changes in blood chemistry, liver, and nephrology of the kidney. The GABA level estimation in the whole brain of mice was performed to predict the mechanistic study of the selected compounds.

Xanthotoxin enhances the anticonvulsant potency of levetiracetam and valproate in the 6-Hz corneal stimulation model in mice.

Xanthotoxin (8-methoxypsoralen; XANT) is a furanocoumarin that has many biological properties, including antiepileptic activity. This study evaluated the effect of XANT on the ability of classical and novel antiepileptic drugs to prevent seizures evoked by the 6-Hz corneal stimulation-induced seizure model, which is thought to be an experimental model of psychomotor (limbic) seizures in humans. XANT (50 mg/kg, administered i.p.) significantly potentiated the anticonvulsant activity of levetiracetam and valproate, decreasing their median effective dose (ED50 ) values from 19.37 to 2.83 mg/kg (P < 0.01) for levetiracetam and from 92.89 to 44.44 mg/kg (P < 0.05) for valproate. Neither XANT (50 mg/kg) alone nor its combination with the anticonvulsant drugs (at their ED50 values from the 6-Hz test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; and grip strength and passive avoidance tests, respectively. Measurement of total brain antiepileptic drug concentrations revealed that XANT (50 mg/kg) had no impact on levetiracetam total brain concentrations, indicating the pharmacodynamic nature of interaction between these antiepileptic drugs in the mouse 6-Hz model. However, XANT (50 mg/kg, i.p.) significantly increased total brain concentrations of valproate (P < 0.01), indicating the pharmacokinetic nature of interactions between drugs. XANT in combination with levetiracetam exerts beneficial anticonvulsant pharmacodynamic interactions in the 6-Hz mouse psychomotor seizure model.

C-11, a New Antiepileptic Drug Candidate: Evaluation of the Physicochemical Properties and Impact on the Protective Action of Selected Antiepileptic Drugs in the Mouse Maximal Electroshock-Induced Seizure Model.

C-11 is a hybrid compound derived from 2-(2,5-dioxopyrrolidin-1-yl) propanamide, with a wide spectrum of anticonvulsant activity and low neurotoxicity. The aim of this study was to determine the effects of C-11 on the protective action of various antiepileptic drugs (i.e., carbamazepine CBZ, lacosamide LCM, lamotrigine LTG, and valproate VPA) against maximal electroshock-induced seizures (MES) in mice, as well as its neuroprotective and physicochemical/pharmacokinetic properties. Results indicate that C-11 (30 mg/kg, i.p.) significantly enhanced the anticonvulsant action of LCM (p < 0.001) and VPA (p < 0.05) but not that of CBZ and LTG in the MES test. Neither C-11 (30 mg/kg) alone nor its combination with other anticonvulsant drugs (at their ED50 values from the MES test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength and passive avoidance tests, respectively. Pharmacokinetic characterization revealed that C-11 had no impact on total brain concentrations of LCM or VPA in mice. Qualitative analysis of neuroprotective properties of C-11, after a single administration of pilocarpine, revealed no protective effect of this substance in the tested animals. Determination of physicochemical descriptors showed that C-11 meets the drug-likeness requirements resulting from Lipinski and Veber’s rules and prediction of gastrointestinal absorption and brain penetration, which is extremely important for the CNS-active compounds.

Augmentation Index Is Inversely Associated with Skeletal Muscle Mass, Muscle Strength, and Anaerobic Power in Young Male Adults: A Preliminary Study

Arterial stiffness is associated with an increased risk of cardiovascular disease. Previous studies have shown that there is a negative correlation between arterial stiffness and variables such as skeletal muscle mass, muscular strength, and anaerobic power in older individuals. However, little research has been undertaken on relationships in healthy young adults. This study presents a preliminary research that investigates the association between arterial stiffness and muscular factors in healthy male college students. Twenty-three healthy young males (23.9 ± 0.5 years) participated in the study. The participants visited the laboratory, and variables including body composition, blood pressure, arterial stiffness, blood parameters, grip strength, and anaerobic power were measured. Measurements of augmentation index (AIx) and brachial-ankle pulse wave velocity (baPWV) were performed to determine arterial stiffness. There were significant positive correlations among skeletal muscle mass, muscle strength, and anaerobic power in healthy young adult males. AIx was negatively associated with a skeletal muscle mass (r = −0.785, p &lt; 0.01), muscular strength (r = −0.500, p &lt; 0.05), and anaerobic power (r = −0.469, p &lt; 0.05), respectively. Likewise, AIx@75 corrected with a heart rate of 75 was negatively associated with skeletal muscle mass (r = −0.738, p &lt; 0.01), muscular strength (r = −0.461, p &lt; 0.05), and anaerobic power (r = −0.420, p &lt; 0.05) respectively. However, the baPWV showed no correlation with all muscular factors. Our findings suggest that maintaining high levels of skeletal muscle mass, muscular strength, and anaerobic power from relatively young age may lower AIx.

Usefulness of Handgrip Strength to Predict Mortality in Patients With Coronary Artery Disease

Handgrip strength (HGS) is a validated and simple technique to estimate skeletal muscular strength. Whether HGS is a predictor of overall mortality in patients with established coronary artery disease (CAD) is not known, this question is therefore addressed in the present study. We prospectively investigated a cohort of 691 patients with angiographically proven CAD. HGS was measured at baseline, and all-cause death as well as cardiovascular events was recorded over a period of up to 12 years. During a follow-up time of 9.2 ± 3.1 years, 31.3% (n = 216) of the study participants died. Further, 27.8% (n = 192) suffered major cardiovascular events and 56.6% (n = 391) any cardiovascular event. Cox proportional hazard model analysis showed a reduced mortality risk with higher HGS univariately (hazard ratio [HR] for each 5 kg increase in HGS 0.87 [95% confidence interval 0.82 to 0.92]; p <0.001), after adjustment for age and gender (HR 0.86 [0.79 to 0.94]; p = 0.001), and after further adjustment for conventional cardiovascular risk factors (HR 0.86 [0.79 to 0.94]; p = 0.001). Similarly, high HGS was protective of major cardiovascular events as well as of total cardiovascular events (HRs in the fully adjusted model 0.86 [0.78 to 0.94]; p = 0.002 and 0.89 [0.83 to 0.96]; p = 0.002, respectively). From these data, we conclude that HGS is an independent predictor of overall survival and of cardiovascular events in patients with CAD.

Beta-hydroxy-beta-methylbutyrateの摂取と筋力運動の併用が閉経後女性の骨格筋量および筋力に及ぼす効果に関する予備的研究：ランダム化クロスオーバー試験

Beta-hydroxy-beta-methylbutyrateの摂取と筋力運動の併用が閉経後女性の骨格筋量および筋力に及ぼす効果に関する予備的研究：ランダム化クロスオーバー試験

Effects of Protein Intake Beyond Habitual Intakes Associated With Resistance Training on Metabolic Syndrome-Related Parameters, Isokinetic Strength, and Body Composition in Older Women.

The objective of this study was to investigate the effects of protein intake beyond habitual intakes associated with resistance training on metabolic syndrome (MetS)-related parameters, isokinetic strength, and body composition in health older women. A total of 30 older women (68.8 ± 4.3years) participated in this investigation and were assigned to receive 35g of whey protein or placebo combined with resistance training, over 12-weeks, three times per week. Blood samples, blood pressure, dietary intake, strength, and body composition were assessed before and after the intervention period. Two-way analysis of variance for repeated measures was applied for comparisons. Both groups improved the skeletal muscle mass, muscular strength, waist circumference, triglycerides, high-density lipoprotein, glucose, resistance, reactance, and MetS Z-score risk. However, the improvements in skeletal muscle mass, waist circumference, and MetS Z-score risk were significantly greater in protein group when compared with control group. Moreover, protein group significantly decreased %body fat when compared with control group. Higher protein intake combined with resistance training promoted greater improvements in skeletal muscle mass, %body fat, waist circumference, and MetS Z-score risk in older women.

Effects of Whey Protein Supplementation Pre- or Post-Resistance Training on Muscle Mass, Muscular Strength, and Functional Capacity in Pre-Conditioned Older Women: A Randomized Clinical Trial.

Aging is associated with sarcopenia and dynapenia, with both processes contributing to functional dependence and mortality in older adults. Resistance training (RT) and increased protein intake are strategies that may contribute to health improvements in older adults. Therefore, the aim was to investigate the effects of whey protein (WP) supplementation consumed either immediately pre- or post-RT on skeletal muscle mass (SMM), muscular strength, and functional capacity in pre-conditioned older women. Seventy older women participated in this investigation and were randomly assigned to one of three groups: whey protein pre-RT and placebo post-RT (WP-PLA, n = 24), placebo pre-RT and whey protein post-RT (PLA-WP, n = 23), and placebo pre- and post-RT (PLA-PLA, n = 23). Each group ingested 35 g of WP or PLA. The RT program was carried out over 12 weeks (three times per week; 3 × 8–12 repetition maximum). Body composition, muscular strength, functional capacity, and dietary intake were assessed pre- and post-intervention. Two-way analysis of covariance (ANCOVA) for repeated measures, with baseline scores as covariates were used for data analysis. A time vs. group interaction (p < 0.05) was observed with WP-PLA and PLA-WP presenting greater increases compared with PLA-PLA for SMM (WP-PLA = 3.4%; PLA-WP = 4.2%; PLA-PLA = 2.0%), strength (WP-PLA = 8.1%; PLA-WP = 8.3%; PLA-PLA = 7.0%), and the 10-m walk test (WP-PLA = −10.8%; PLA-WP = −11.8%; PLA-PLA = −4.3%). Whey protein supplementation was effective in promoting increases in SMM, muscular strength, and functional capacity in pre-conditioned older women, regardless of supplementation timing. This trial was registered at ClinicalTrials.gov: NCT03247192.

Cytisine inhibits the protective activity of various classical and novel antiepileptic drugs against 6Hz-induced psychomotor seizures in mice.

Cytisine (CYT) is a partial agonist of brain α4β2 nicotinic acetylcholine receptors widely used in Central/Eastern Europe for smoking cessation. This study evaluated the effect of CYT on the ability of classical and novel antiepileptic drugs to prevent seizures evoked by the 6-Hz test, a model of psychomotor seizures in mice thought as a model of drug-resistant seizures. CYT administered intraperitoneally (i.p.) in a dose of 2mgkg-1 significantly inhibited the anticonvulsant activity of lacosamide, levetiracetam, and pregabalin, increasing their median effective doses 50 (ED50) values from 6.88 to 10.52mgkg-1 (P<0.05) for lacosamide, from 22.08 to 38.26mgkg-1 (P<0.05) for levetiracetam, and from 40.48 to 64.61mgkg-1 (P<0.01) for pregabalin, respectively. There were no significant changes in total brain concentrations of lacosamide, levetiracetam, and pregabalin following CYT i.p. administration. CYT administered in a dose of 2mgkg-1 failed to change the protective action of clobazam, clonazepam, phenobarbital, tiagabine, and valproate in the 6-Hz test. Neither CYT (2mgkg-1) alone nor its combination with the anticonvulsant drugs (at their ED50 values from the 6-Hz test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; and grip strength and passive avoidance tests, respectively. CYT-evoked alterations in the protection provided by some antiepileptic drugs against seizures can be of serious concern for epileptic smokers, who might demonstrate therapeutic failure to lacosamide, levetiracetam, and pregabalin, resulting in possible breakthrough seizure attacks.

Preliminary study on appendicular skeletal muscle mass, muscular strength and function in the elderly

Objective To investigate the status of appendicular skeletal muscle mass, muscular strength and changes of muscle function in the elderly in Shanghai. Methods A total of 402 participants were recruited from physical examination centers in our hospital. Appendicular skeletal muscle mass (ASM) was measured by bioelectrical impedance analysis (BIA). The ASM index (ASM/height2) was calculated. Muscle function was measured by testing gait speed (m/s). Muscle strength was measured by handgrip strength (HGS) using an electronic hand dynamometer. Results The ASM index significantly declined with age in both men and women (F=2.133 and 3.124, both P=0.000). For women, there was a significant difference in HGS only between the youngest age group (aged 60~69 years) and the oldest age group (aged≥80 years)(P=0.005). For men, HGS was significantly different among all age groups (all P 0.05), while the significant differences in gait speed were observed between the 70-79 years old groups and ≥80 year old group in both genders (both P<0.05). Conclusions Appendicular skeletal muscle mass, strength and function are decreased with ageing in the elderly. The muscle strength decreases faster in the elderly man than in the elderly woman, and muscle function decreases significantly in both genders after 80 years old. Key words: Muscular diseases; Hand strength

Anticonvulsant activity of melatonin, but not melatonin receptor agonists Neu-P11 and Neu-P67, in mice

The anticonvulsant activity of melatonin (MLT) have been tested in several in vivo models and against different convulsive stimuli. Although MLT exerts high affinity towards melatonin receptors (MTs), the potential usefulness in the treatment of epilepsy is limited mainly due to its short half-life. Therefore, the purpose of the present study was to compare the anticonvulsant properties of novel MT agonists Neu-P11 and Neu-P67 with MLT in mice. The anticonvulsant activity of tested compounds was evaluated in pentylenetetrazole-(PTZ) and electrically-induced convulsions. The effect of studied compounds on motor coordination and skeletal muscular strength in mice was assessed in the chimney test and grip test, respectively. The locomotor activity after administration of the tested compounds was also evaluated. In the MEST and 6Hz tests, only MLT (50 and 100mg/kg, i.p.) significantly increased the seizure threshold. The i.p. administration of MLT (100mg/kg) and Neu-P67 (200mg/kg) resulted in a significantly elevated PTZ seizure threshold for forelimbs tonus. The compounds did not affect muscle strength. No alterations in motor coordination were noted. However, the locomotor activity was significantly decreased after administration of all tested compounds. Our study confirms the anticonvulsant potency of MLT and shows that novel synthetic MT agonists Neu-P11 and Neu-P67 have no effect on epileptic seizures in mice. Our data suggest that the activation of MT can be used in the treatment of seizures, but further pharmacological characterization is needed to understand the anticonvulsant activity of MLT and to design efficient MT-targeting antiepileptic drugs.

Effect of Progressive Resistance Training on Measures of Skeletal Muscle Hypertrophy, Muscular Strength and Health-Related Quality of Life in Patients with Chronic Kidney Disease: A Systematic Review and Meta-Analysis

Skeletal muscle wasting resulting in reduced muscular strength and health-related quality of life (HR-QOL) is common in chronic kidney disease (CKD) and may be reversed with progressive resistance training (PRT). Therefore, we systematically assessed the effect of PRT on measures of skeletal muscle hypertrophy, muscular strength and HR-QOL in this cohort to inform clinical practice and guidelines. We performed a systematic review and meta-analysis. We included randomised controlled trials (RCTs) that investigated the independent effect of PRT (>6 weeks) on measures of skeletal muscle hypertrophy [muscle mass or cross-sectional area (CSA)], muscular strength and/or HR-QOL in adults with CKD. The standardised mean difference (SMD) from each study was pooled to produce an overall estimate of effect and associated 95% confidence interval (95% CI) between treatment and control groups on primary outcomes. Seven RCTs in 271 patients with Stage 3-5 CKD yielded seven studies on muscular strength (N = 249), six studies on total body muscle mass (N = 200) and six studies on HR-QOL (N = 223). PRT significantly improved standardised muscular strength [SMD 1.15 (95% CI 0.80-1.49)] and HR-QOL [SMD 0.83 (95% CI 0.51-1.16)], but not total body muscle mass [SMD 0.29 (95% CI -0.27 to 0.86)] in our primary analysis. However, secondary analysis of six studies showed that PRT induced significant muscle hypertrophy of the lower extremities (leg mass, or mid-thigh or quadriceps CSA) [SMD 0.43 (95% CI 0.11-0.76)], a pertinent analysis given that most studies implemented lower-body PRT only. Robust evidence from RCTs indicates that PRT can induce skeletal muscle hypertrophy and increase muscular strength and HR-QOL outcomes in men and women with CKD. Therefore, clinical practice guidelines should be updated to inform clinicians on the benefits of PRT in this cohort.

Effects of WIN 55,212-2 (a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of various classical antiepileptic drugs in the mouse 6 Hz psychomotor seizure model

The aim of this study was to characterize the influence of WIN 55,212-2 (WIN—a non-selective cannabinoid CB1 and CB2 receptor agonist) on the anticonvulsant effects of various classical antiepileptic drugs (clobazam, clonazepam, phenobarbital and valproate) in the mouse 6 Hz-induced psychomotor seizure model. Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via ocular electrodes. Drug-related adverse effects were ascertained by use of the chimney test (evaluating motor performance), step-through passive avoidance task (assessing learning) and grip-strength test (evaluating skeletal muscular strength). Total brain concentrations of antiepileptic drugs were measured by fluorescence polarization immunoassay to ascertain any pharmacokinetic contribution to the observed antiseizure effect. Results indicate that WIN (5 mg/kg, administered intraperitoneally) significantly enhanced the anticonvulsant action of clonazepam (P < 0.001), phenobarbital (P < 0.05) and valproate (P < 0.05), but not that of clobazam in the mouse 6 Hz model. Moreover, WIN (2.5 mg/kg) significantly potentiated the anticonvulsant action of clonazepam (P < 0.01), but not that of clobazam, phenobarbital or valproate in the 6 Hz test in mice. None of the investigated combinations of WIN with antiepileptic drugs was associated with any concurrent adverse effects with regard to motor performance, learning or muscular strength. Pharmacokinetic experiments revealed that WIN had no impact on total brain concentrations of antiepileptic drugs in mice. These preclinical data would suggest that WIN in combination with clonazepam, phenobarbital and valproate is associated with beneficial anticonvulsant pharmacodynamic interactions in the mouse 6 Hz-induced psychomotor seizure test.

Effects of WIN 55,212-2 mesylate on the anticonvulsant action of lamotrigine, oxcarbazepine, pregabalin and topiramate against maximal electroshock-induced seizures in mice

The aim of this study was to determine the effect of WIN 55,212-2 mesylate (WIN – a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of four second-generation antiepileptic drugs (lamotrigine, oxcarbazepine, pregabalin and topiramate) in the mouse maximal electroshock seizure model. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25mA, 500V, 50Hz, 0.2s stimulus duration) delivered via auricular electrodes. Drug-related adverse effects were ascertained by use of the chimney test (evaluating motor performance), the step-through passive avoidance task (assessing long-term memory) and the grip-strength test (evaluating skeletal muscular strength). Total brain concentrations of antiepileptic drugs were measured by high-pressure liquid chromatography to ascertain any pharmacokinetic contribution to the observed antiseizure effect. Results indicate that WIN (5mg/kg, i.p.) significantly enhanced the anticonvulsant action of lamotrigine (P<0.05), pregabalin (P<0.001) and topiramate (P<0.05), but not that of oxcarbazepine in the maximal electroshock-induced tonic seizure test in mice. Furthermore, none of the investigated combinations of WIN with antiepileptic drugs were associated with any concurrent adverse effects with regards to motor performance, long-term memory or muscular strength. Pharmacokinetic characterization revealed that WIN had no impact on total brain concentrations of lamotrigine, oxcarbazepine, pregabalin and topiramate in mice. These preclinical data would suggest that WIN in combination with lamotrigine, pregabalin and topiramate is associated with beneficial anticonvulsant pharmacodynamic interactions in the maximal electroshock-induced tonic seizure test.

Combination Therapy of Piperine and Phenytoin in Maximal Electroshock Induced Seizures in Mice: Isobolographic and Biochemical Analysis

The present study was aimed to characterize the anticonvulsant effects of piperine in combination with well established antiepileptic drug (AED) phenytoin, in the mouse maximal electroshock (MES)-induced seizure model by using the type I isobolographic analysis for non-parallel dose-response relationship curves (DRRCs). Potential adverse-effect profiles of interactions of phenytoin with piperine at the fixed-ratio of 1:1 from the MES test with respect to long-term memory and skeletal muscular strength were evaluated along with free plasma concentration of piperine and phenytoin. Parameters of oxidative stress (glutathione, malondialdehyde), brain serotonin and serum calcium levels were also determined to probe the mechanism involved in the interaction. Test of parallelism revealed that 2 drugs were associated with non-parallel dose response effects, hence only one fixed ratio combination (1:1) was evaluated which displayed additive interaction between the 2 drugs with a slight tendency towards superadditivity. Free plasma concentrations of piperine and phenytoin revealed no significant changes in their concentrations when the drugs were combined at the fixed-ratio of 1:1. In combination, neither long-term memory nor skeletal muscular strength was impaired. Analysis of biochemical parameters showed that the piperine alone or in combination with phenytoin successfully reversed the parameters of oxidative stress and increased brain serotonin levels as compared to MES group. However, no significant alteration in the serum calcium levels was observed by any treatment. In conclusion, the combination displayed additive interaction and slight tendency towards synergistic potential with protection towards side effects associated with AED therapy and is worthy of consideration for further investigations.

The mu-opioid receptor-selective peptide antagonists, antanal-1 and antanal-2, produce anticonvulsant effects in mice

The activation of the mu-opioid receptors (MOR) in the central nervous system has a proconvulsant effect and seizures are a common side effect of high doses of short acting opioids, like morphine or fentanyl. However, the correct assessment of the role of MOR blockade in the initiation and propagation of epilepsy was hampered by the lack of potent and selective MOR antagonists. In this study we aimed at characterizing the effect of MOR blockade on the seizure threshold in mice using recently developed selective antagonists antanal-1 and antanal-2 and a classical MOR antagonist, β-funaltrexamine (β-FNA). The effect of the centrally administered MOR antagonists was characterized in the maximal electroshock seizure threshold (MEST), the 6 Hz psychomotor seizure threshold and the intravenous pentylenetetrazole (PTZ) seizure threshold test in mice. The acute effect of the studied compounds on skeletal muscular strength in mice was quantified in the grip-strength test. Antanal-1 and antanal-2 (30 and 50 nmol/mouse, i.c.v.), but not β-FNA significantly increased the seizure threshold in the MEST test in mice. In the 6-Hz test, all tested MOR antagonists significantly increased the psychomotor seizure threshold and the most potent anticonvulsant effect was observed for antanal-2 (2, 10 and 30 nmol/mouse, i.c.v.). The i.c.v. administration of β-FNA (10 and 30 nmol/mouse, i.c.v.), antanal-1 and antanal-2 (both 30, 50 and 100 nmol/mouse, i.c.v.) did not produce any significant effect on PTZ seizure threshold, the generalized clonus or the forelimbs tonus. All tested compounds did not affect muscle strength, as determined in the grip strength test. Our study demonstrated that the novel MOR-selective antagonists antanal-1 and antanal-2 displayed a potent and dose-dependent anticonvulsant action involving non-GABA-ergic, but some other pathways and mechanisms in animal models of epileptic seizures. We suggest that antanals are promising drug templates for future therapeutics, which may be used in the treatment of epilepsy in humans.