Mirogabalin, a novel ligand for α2δ subunit of voltage-gated calcium channels, improves cognitive impairments in repeated intramuscular acidic saline injection model rats, an experimental model of fibromyalgia.

Mirogabalin is a novel potent and selective ligand for the α2δ subunit of voltage-gated calcium channels, and shows potent and sustained analgesic effects in neuropathic pain and fibromyalgia models. Fibromyalgia is often associated with multiple comorbid symptoms, such as anxiety, depression and cognitive impairment. In the present study, we investigated the effects of mirogabalin on cognitive impairments in an experimental animal model for fibromyalgia, repeated intramuscular acidic saline injection model (Sluka model) rats. Male rats received two repeated intramuscular injections of pH 4 acidic saline into their gastrocnemius muscle. After developing mechanical hypersensitivity as identified in the von Frey test, the animals received the test substance orally once daily for 13 days and were subjected to four cognitive function tests, (Y-maze, novel object recognition, Morris water maze and step-through passive avoidance). Sluka model rats showed cognitive impairments in all four tests. Oral administration of mirogabalin (3 and 10 mg/kg) improved the cognitive impairments in these rats. In conclusion, mirogabalin improved the impaired cognitive function in Sluka model rats. It may thus also alleviate cognitive impairments as well as painful symptoms in fibromyalgia patients.

Nimodipine down-regulates CGRP expression in the rat trigeminal nucleus caudalis.

L-type calcium channel blockers like verapamil are used in the prophylaxis of migraine. However, their effect on the expression of CGRP in the trigeminal nucleus caudalis (TNC) is unknown. It is important because an earlier study had shown that olcegepant, a CGRP receptor antagonist, acts at the level of the trigeminal spinal nucleus rather than the trigeminal ganglia. Nimodipine was used in the present study as it crosses the blood-brain barrier. The objective of the study was to determine the pattern of expression of calcitonin gene-related peptide (CGRP) in the TNC after administration of nimodipine and/or morphine. Wistar rats were injected with saline, morphine, nimodipine or morphine + nimodipine for 14 days. Subsequently, the lowest part of the medulla oblongata containing the spinal nucleus was removed and processed for immunohistochemical localization of CGRP. The density of expression was quantified using Image J software. The results were statistically analyzed. CGRP expression was noted over the superficial part of the TNC, which decreased significantly after nimodipine administration. Conversely, morphine produced an up-regulation. The expression was unchanged with reference to saline in the morphine + nimodipine treated group. Decreased expression of CGRP in the trigeminal nucleus caudalis after nimodipine is being reported for the first time. Also, whether CGRP expression can be used as a marker for predicting the therapeutic efficacy of an anti-migraine drug is currently being investigated.

L-type calcium channels and calcium/calmodulin-dependent kinase II differentially mediate behaviors associated with nicotine withdrawal in mice.

Smoking is a widespread health problem. Because the nicotine withdrawal syndrome is a major contributor to continued smoking and relapse, it is important to understand the molecular and behavioral mechanisms of nicotine withdrawal to generate more effective smoking cessation therapies. Studies suggest a role for calcium-dependent mechanisms, such as L-type calcium channels and calcium/calmodulin-dependent protein kinase II (CaMKII), in the effects of nicotine dependence; however, the role of these mechanisms in nicotine-mediated behaviors is unclear. Thus, the goal of this study was to elucidate the role of L-type calcium channels and CaMKII in nicotine withdrawal behaviors. Using both pharmacological and genetic methods, our results show that L-type calcium channels are involved in physical, but not affective, nicotine withdrawal behaviors. Although our data do provide evidence of a role for CaMKII in nicotine withdrawal behaviors, our pharmacological and genetic assessments yielded different results concerning the specific role of the kinase. Pharmacological data suggest that CaMKII is involved in somatic signs and affective nicotine withdrawal, and activity level is decreased after nicotine withdrawal, whereas the genetic assessments yielded results suggesting that CaMKII is involved only in the anxiety-related response, yet the kinase activity may be increased after nicotine withdrawal; thus, future studies are necessary to clarify the precise behavioral specifics of the relevance of CaMKII in nicotine withdrawal behaviors. Overall, our data show that L-type calcium channels and CaMKII are relevant in nicotine withdrawal and differentially mediate nicotine withdrawal behaviors.

Levosimendan in patients with low-output heart failure: lessons from the LIDO trial.

The novel calcium sensitizer levosimendan improves myocardial contractility without causing an increase in intracellular calcium and cyclic adenosine monophosphate concentrations. It also has a vasodilator action due to an opening of the adenosine triphosphate-sensitive potassium channels. In a double-blind clinical trial levosimendan was compared with dobutamine in 203 patients with severe low-output congestive heart failure. A 24-hour infusion of these inotropic drugs was administered to increase the cardiac output by at least 30% together with a decrease in the pulmonary capillary wedge pressure by > or = 25%. The pre-defined hemodynamic improvement was achieved in 28% of patients receiving levosimendan compared to only 15% with dobutamine (p = 0.022). Levosimendan also reduced the 1- and 6-month mortality more than dobutamine (7.8 vs 17%, p = 0.045 and 26 vs 38%, p = 0.029, respectively). Levosimendan produced less myocardial ischemia and cardiac arrhythmias than dobutamine. Calcium sensitizers offer a new therapeutic possibility in patients with decompensated low-output heart failure.

Preliminary clinical experience with the repetitive administration of levosimendan in patients with end-stage heart failure.

We present our preliminary clinical experience with the initial and repetitive administration of the novel inotropic agent levosimendan in a cohort of 20 patients with end-stage heart failure who were acutely decompensated or whose symptoms were refractory to the usual pharmacological treatments thus necessitating hospitalization. Repetitive levosimendan infusions were administered to 9 patients (minimum 2, maximum 8 pulses). The effects of this therapy on the symptomatic status, vital signs, hemodynamic performance and clinical outcomes are discussed.