Search

Friedreich ataxia is a progressive autosomal recessive neurodegenerative disorder characterized by ataxia, dyscoordination, and cardiomyopathy. A subset of patients with Friedreich ataxia have elevated levels of serum cardiac troponin I, but associations with disease outcomes and features of cardiomyopathy remain unclear. In this study, we characterized clinically obtained serum cardiac biomarker levels including troponin I, troponin T, and B-type natriuretic peptide in subjects with Friedreich ataxia and evaluated their association with markers of disease. While unprovoked troponin I levels were elevated in 36% of the cohort, cTnI levels associated with a cardiac event (provoked) were higher than unprovoked levels. In multivariate linear regression models, younger age predicted increased troponin I values, and in logistic regression models younger age, female sex, and marginally longer GAA repeat length predicted abnormal troponin I levels. In subjects with multiple assessments, mean unprovoked troponin I levels decreased slightly over time. The presence of abnormal troponin I values and their levels were predicted by echocardiographic measures of hypertrophy. In addition, troponin I levels predicted long-term markers of clinical cardiac dysfunction over time to a modest degree. Consequently, troponin I values provide a marker of hypertrophy but only a minimally predictive biomarker for later cardiac manifestations of disease such as systolic dysfunction or arrhythmia., (Copyright © 2023. Published by Elsevier B.V.)

Adenosine (ADO) is an inhibitory neuromodulator that can increase the nociceptive threshold in animals exposed to a variety of noxious stimuli. Inhibition of the ADO-metabolizing enzyme, ADO kinase (AK), provides a means of locally enhancing extracellular ADO concentrations. In the present study, the AK inhibitors 5'-amino,5'-deoxy-ADO (NH2dADO), 5-iodotubercidin (5-IT), and 5'-deoxy,5-iodotubercidin (5'd-5IT) were examined for their analgesic efficacy in the hot-plate model of acute somatic nociception. Control and drug-treated adult male mice were placed on a 55 degrees C hot plate and the latency to the 10th jump was recorded via a computer driven infrared-beam photosensor. All three AK inhibitors were found to significantly increase jump latencies in a dose-dependent fashion. 5'd-5IT was the most potent AK inhibitor (approx. ED50 value = 1 micromol/kg, IP), followed by 5-IT (ED50 value = 10 micromol/kg, IP), and NH2dADO (ED50 value = 100 micromol/kg, IP). 5'd-5IT was found to be more potent and equally efficacious to morphine (ED50 value = 5.2 micromol/kg, IP) in this assay. In a model of persistent chemical pain, the phenyl-p-quinone-induced abdominal constriction assay, 5'd-5IT (ED50 value = 1.5 micromol/kg, SC) and morphine (ED50 value = 3.0 micromol/kg, SC) dose dependently reduced nociception. Pretreatment of mice with either the nonselective ADO receptor antagonist, theophylline (56 micromol/kg, IP), but not the peripherally acting antagonist, 8-(p-sulfophenyl)-theophylline (8-PST, 200 micromol/kg, IP) significantly attenuated the antinociceptive effects of 5'd-5IT in the hot-plate assay. Furthermore, the antinociceptive effects of 5'd-5IT were completely blocked by an ADO A1 receptor selective antagonist, DPCPX, while an ADO A2A receptor selective antagonist, ZM 241385, showed markedly less antagonist activity. The analgesic effects of 5'd-5IT were not blocked by the opioid receptor antagonist naloxone; however, 5'd-5IT could produce additive analgesic effects with morphine when both compounds were administered in combination. The apparent efficacy of 2.5 micromol/kg, IP, of 5'd-5IT was not significantly altered following the repeated administration of this dose twice daily for 4 days. The present data provide evidence for an antinociceptive action of AK inhibitors in the hot-plate test, which, at least for 5'd-5IT, is mediated by an enhancement of ADO's actions at the ADO A1 receptor subtype, is nonopioid in nature, and which does not exhibit tolerance following repeated administration.

The experiments in the present study were designed to determine if the activity, temperature, and analgesic effects of (+/-)-epibatidine treatment could be dissociated. Initially (i.e., 15 min) (+/-)-epibatidine treatment (0.1 mumol/kg = 28 micrograms/kg, IP) impaired rotorod performance, decreased activity, decreased temperature, and increased jump latency (e.g., analgesic effect). For the remaining time points measured (i.e., 30, 60, and 120 min), activity and temperature remained significantly reduced. In contrast, by 120 min (+/-)-epibatidine's effects on rotorod performance and analgesia (jump latency) were not observed. When administered after (+/-)-epibatidine (0.05 mumol/kg, IP), mecamylamine treatment (5 mumol/kg = 1 mg/kg, IP) produced a potentiation of analgesia. This potentiation effect was not observed on activity and temperature measures. The effect of (+/-)-epibatidine treatment (0.1 mumol/kg, IP) was also determined in mice with central nicotinic receptor blockade induced by treatment with chlorisondamine (23 mumol/kg = 10 mg/kg, IP). An (+/-)-epibatidine-induced reduction in activity was not attenuated in chlorisondamine-treated mice and only a minimal effect was observed on (+/-)-epibatidine-induced hypothermia in chlorisondamine-treated mice. In contrast, in chlorisondamine-treated mice (+/-)-epibatidine's analgesic effect was attenuated. Taken together, these data suggest that various centrally mediated effects of (+/-)-epibatidine can be dissociated.