The effect of chronic exercise training and acute exercise on power spectral analysis of heart rate variability.

Moderate to vigorous physical activity performed regularly is cardioprotective and reduces all-cause mortality, concomitant with increased resting heart rate variability (HRV). However, there are contradictory reports regarding the effects of chronic and acute exercise on nocturnal HRV in those performing exercise well-beyond physical activity guidelines. Therefore, the purpose of this study was to compare the power spectral analysis components of HRV in middle-aged endurance athletes (EA) and recreationally active individuals (REC) and explore acute exercise effects in EA. A total of 119 EA (52, 49-57 years) and 32 REC (56, 52-60 years) were recruited to complete 24 h Holter monitoring (GE SEER 1000) in the absence of exercise. Fifty one EA (52, 49-57 years) then underwent 24 h Holter monitoring following an intense bout of endurance exercise. Power spectral HRV analysis was completed hourly and averaged to quantify morning (1000-1200 h), evening (1900-2100 h), and nocturnal (0200-0400 h) HRV. EA had greater very low frequency (VLF) and low frequency (LF) (both p < 0.001) compared to REC. LF/high frequency (HF) was greater in EA at 0200-0400 h (p = 0.04). Among all participants, the change in HR and HF from 1000-1200 to 0200-0400 h was negatively correlated (r = -0.47, p < 0.001). Following acute exercise in EA, only nocturnal HRV was assessed. VLF (p < 0.001) and HF (p = 0.008) decreased, while LF/HF increased (p = 0.02). These results suggest that in EA, both long-term and acute exercises increase nocturnal sympathovagal activity through an increase in LF and decrease in HF, respectively. Further work is required to understand the mechanism underlying reduced nocturnal HRV in middle-aged EA and the long-term health implications.

Cardiac remodeling in middle-aged endurance athletes: relation between signal-averaged electrocardiogram and LV mass.

The relationship between structural and electrical remodeling in the heart, particularly after long-standing endurance training, remains unclear. Signal-averaged electrocardiogram (SAECG) may provide a more sensitive method to evaluate cardiac remodeling than a 12-lead electrocardiogram (ECG). Accurate measures of electrical function (SAECG filtered QRS duration (fQRSd) and late potentials (LP) and left-ventricular (LV) mass (cardiac magnetic resonance, CMR) can allow an assessment of structural remodeling and QRS prolongation. Endurance athletes (45-65 yr old, >10 yr of endurance sport), screened to exclude cardiac disease, had standardized 12-lead ECG, SAECG, resting echocardiogram (ECHO), and CMR performed. SAECG fQRSd was correlated with QRS duration on the 12-lead ECG, and ECHO and CMR-derived LV mass. Participants (n = 82, 67% male, mean age: 54 ± 6 yr, mean V̇o2max: 50 ± 7 mL/kg/min) had a CMR-derived LV mass of 118 ± 28 g/m2 and a fQRSd of 112 ± 8 ms (46% had abnormal fQRSd (>114 ms), and 51% met clinical threshold for abnormal SAECG). fQRSd was positively correlated with the 12-lead ECG QRS duration (r = 0.83), ECHO-derived LV mass (r = 0.60), CMR-derived LV mass (r = 0.58) and LV end-diastolic volume (r = 0.63, P < 0.001 for all). fQRSd had higher correlations with ECHO and CMR-derived LV mass than 12-lead ECG (P < 0.0008 and P < 0.0005, respectively). In conclusion, in a healthy cohort of middle-aged endurance athletes, the SAECG is often abnormal by conventional criteria, and is correlated with structural remodeling, but CMR evaluation does not indicate pathologic structural remodeling. SAECG fQRSd is superior to the 12-lead ECG for the electrocardiographic evaluation of LV mass.NEW & NOTEWORTHY Study findings indicate that a positive correlation exists between electrical (SAECG fQRSd) and structural indices (LV mass) in middle-aged endurance athletes with normal physiological LV adaptation, in the absence of known cardiac pathology. SAECG fQRSd may also provide an alternative, superior method for identifying increased LV mass compared to other 12-lead ECG criteria.

Cytochrome P450 binding studies of novel tacrine derivatives: Predicting the risk of hepatotoxicity.

The 1,2,3,4-tetrahydroacridine derivative tacrine was the first drug approved to treat Alzheimer's disease (AD). It is known to act as a potent cholinesterase inhibitor. However, tacrine was removed from the market due to its hepatotoxicity concerns as it undergoes metabolism to toxic quinonemethide species through the cytochrome P450 enzyme CYP1A2. Despite these challenges, tacrine serves as a useful template in the development of novel multi-targeting anti-AD agents. In this regard, we sought to evaluate the risk of hepatotoxicity in a series of C9 substituted tacrine derivatives that exhibit cholinesterase inhibition properties. The hepatotoxic potential of tacrine derivatives was evaluated using recombinant cytochrome (CYP) P450 CYP1A2 and CYP3A4 enzymes. Molecular docking studies were conducted to predict their binding modes and potential risk of forming hepatotoxic metabolites. Tacrine derivatives compound 1 (N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) and 2 (6-chloro-N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) which possess a C9 3,4-dimethoxybenzylamino substituent exhibited weak binding to CYP1A2 enzyme (1, IC50=33.0µM; 2, IC50=8.5µM) compared to tacrine (CYP1A2 IC50=1.5µM). Modeling studies show that the presence of a bulky 3,4-dimethoxybenzylamino C9 substituent prevents the orientation of the 1,2,3,4-tetrahydroacridine ring close to the heme-iron center of CYP1A2 thereby reducing the risk of forming hepatotoxic species.

Structure-activity relationship studies of benzyl-, phenethyl-, and pyridyl-substituted tetrahydroacridin-9-amines as multitargeting agents to treat Alzheimer's disease.

A library of substituted tetrahydroacridin-9-amine derivatives were designed, synthesized, and evaluated as dual cholinesterase and amyloid aggregation inhibitors. Compound 8e (N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) was identified as a potent inhibitor of butyrylcholinesterase (BuChE IC50  = 20 nm; AChE IC50  = 2.2 µm) and was able to inhibit amyloid aggregation (40% inhibition at 25 µm). Compounds 9e (6-chloro-N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine, AChE IC50  = 0.8 µm; BuChE IC50  = 1.4 µm; Aß-aggregation inhibition = 75.7% inhibition at 25 µm) and 11b (6-chloro-N-(3,4-dimethoxyphenethyl)-1,2,3,4-tetrahydroacridin-9-amine, AChE IC50  = 0.6 µm; BuChE IC50  = 1.9 µm; Aß-aggregation inhibition = 85.9% inhibition at 25 µm) were identified as the best compounds with dual cholinesterase and amyloid aggregation inhibition. The picolylamine-substituted compound 12c (6-chloro-N-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroacridin-9-amine) was the most potent AChE inhibitor (IC50  = 90 nm). These investigations demonstrate the utility of 3,4-dimethoxyphenyl substituent as a novel pharmacophore possessing dual cholinesterase inhibition and anti-Aß-aggregation properties that can be used in the design and development of small molecules with multitargeting ability to treat Alzheimer's disease.

Selective inhibition of human acetylcholinesterase by xanthine derivatives: in vitro inhibition and molecular modeling investigations.

The commonly used beverage and psychostimulant caffeine is known to inhibit human acetylcholinesterase enzyme. This pharmacological activity of caffeine is partly responsible for its cognition enhancing properties. However, the exact mechanisms of its binding to human cholinesterases (acetyl and butyrylcholinesterase; hAChE and hBuChE) are not well known. In this study, we investigated the cholinesterase inhibition by the xanthine derivatives caffeine, pentoxifylline, and propentofylline. Among them, propentofylline was the most potent AChE inhibitor (hAChE IC50=6.40 µM). The hAChE inhibitory potency was of the order: caffeine (hAChE IC50=7.25 µM)50 µM) relative to the reference agent donepezil (hBuChE IC50=13.60 µM). Molecular modeling investigations indicate that caffeine binds primarily in the catalytic site (Ser203, Glu334 and His447) region of hAChE whereas pentoxifylline and propentofylline are able to bind to both the catalytic site and peripheral anionic site due to their increased bulk/size, thereby exhibiting superior AChE inhibition relative to caffeine. In contrast, their lack of hBuChE inhibition is due to a larger binding site and lack of key aromatic amino acids. In summary, our study has important implications in the development of novel caffeine derivatives as selective AChE inhibitors with potential application as cognitive enhancers and to treat various forms of dementia.

Investigating the binding interactions of galantamine with ß-amyloid peptide.

The anti-Alzheimer's agent galantamine is known to possess anti-amyloid properties. However the exact mechanisms are not clear. We studied the binding interactions of galantamine with amyloid peptide dimer (Aß(1-40)) through molecular docking and molecular dynamics simulations. Galantamine's binding site within the amyloid peptide dimer was identified by docking experiments and the most stable complex was analyzed by molecular dynamics simulation. These studies show that galantamine was interacting with the central region of the amyloid dimer (Lys16-Ala21) and the C-terminal region (Ile31-Val36) with minimum structural drift of Cα atom in those regions. Strikingly, a significant drift was observed at the turn region from Asp23-Gly29 (Cα atom RMSD=9.2 Å and 11.6 Å at 50 fs and 100 fs respectively). Furthermore, galantamine's binding mode disrupts the key pi-pi stacking interaction between aromatic rings of Phe19 (chain A) and Phe19 (chain B) and intermolecular hydrogen bonds seen in unbound peptide dimer. Noticeably, the azepine tertiary nitrogen of galantamine was in close proximity to backbone CO of Leu34 (distance <3.5 Å) to stabilize the dimer conformation. In summary, the results indicate that galantamine binding to amyloid peptide dimer leads to a significant conformational change at the turn region (Asp23-Gly29) that disrupts interactions between individual ß-strands and promotes a nontoxic conformation of Aß(1-40) to prevent the formation of neurotoxic oligomers.