Voltage-gated ion channels are important mediators of physiological functions in the central nervous system. The cyclic activation of these channels influences neurotransmitter release, neuron excitability, gene transcription, and plasticity, providing distinct brain areas with unique physiological and pharmacological response. A growing body of data has implicated ion channels in the susceptibility or pathogenesis of psychiatric diseases. Indeed, population studies support the association of polymorphisms in calcium and potassium channels with the genetic risk for bipolar disorders (BPDs) or schizophrenia. Moreover, point mutations in calcium, sodium, and potassium channel genes have been identified in some childhood developmental disorders. Finally, antibodies against potassium channel complexes occur in a series of autoimmune psychiatric diseases. Here we report recent studies assessing the role of calcium, sodium, and potassium channels in BPD, schizophrenia, and autism spectrum disorders, and briefly summarize promising pharmacological strategies targeted on ion channels for the therapy of mental illness and related genetic tests.

The skeletal muscle atrophy and sarcopenia are negative prognostic factors in the treatment of the diabetic aged-population. Insulin therapy stimulated protein anabolism in younger but not older patients and failed to prevent atrophy. The insulin- sensitizer glitazones are promising agents against atrophy but the un-favorable benefit/risk profile limits their use. Metformin is an AMPK agonist potentiating insulin actions in the adult human muscle, but not in the aged individuals. The AMPK agonists have the potential to induce atrophy. The KATP channel blockers such as the sulfonylureas and glinide may induce atrophy. Glibenclamide indeed induces atrophy in rat and in human. Within the glinides, repaglinide is the most potent atrophic agent “in vitro” in animals. The GLP-1 and incretins showed beneficial effects in skeletal muscle but their effects on the age-dependent muscle atrophy in human and animals are not known. The novel sodium glucose co-transporter inhibitors may not have been recognized as drug-induced atrophic/anti-atrophic effects. Here we reviewed the effects of the anti-diabetic drugs on the age-related muscle atrophy.

Peripheral neurologic complications are frequent adverse events during oncologic treatments and often lead to dose reduction, administration delays with time elongation of the therapeutic plan and, not least, worsening of patients’ quality of life. Experience skills are required to recognize symptoms and clinical evidences and the collaboration between different health professionals, in particular oncologists and hospital pharmacists, grants a correct management of this undesirable occurrence. Some classes of drugs (platinates, vinca alkaloids, taxanes) typically develop this kind of side effect, but the genesis of chemotherapy-induced peripheral neuropathy is not linked to a single mechanism. This paper aims from one side at summarizing and explaining all the scattering mechanisms of chemotherapy-induced peripheral neuropathy through a detailed literature revision, on the other side at finding new approaches to possible treatments, in order to facilitate the collaboration between oncologists, hematologists and hospital pharmacists.

TheATP‐sensitive K⁺(KATP) channel is an emerging pathway in the skeletal muscle atrophy which is a comorbidity condition in diabetes. The “in vitro” effects of the sulfonylureas and glinides were evaluated on the protein content/muscle weight, fibers viability, mitochondrial succinic dehydrogenases (SDH) activity, and channel currents in oxidative soleus (SOL), glycolitic/oxidative flexor digitorum brevis (FDB), and glycolitic extensor digitorum longus (EDL) muscle fibers of mice using biochemical and cell‐counting Kit‐8 assay, image analysis, and patch‐clamp techniques. The sulfonylureas were: tolbutamide, glibenclamide, and glimepiride; the glinides were: repaglinide and nateglinide. Food and Drug Administration‐Adverse Effects Reporting System (FDA‐AERS) database searching of atrophy‐related signals associated with the use of these drugs in humans has been performed. The drugs after 24 h of incubation time reduced the protein content/muscle weight and fibers viability more effectively inFDBandSOLthan in theEDL. The order of efficacy of the drugs in reducing the protein content inFDBwas: repaglinide (EC50 = 5.21 × 10⁻⁶) ≥ glibenclamide(EC50 = 8.84 × 10⁻⁶) > glimepiride(EC50 = 2.93 × 10⁻⁵) > tolbutamide(EC50 = 1.07 × 10⁻⁴) > nateglinide(EC50 = 1.61 × 10⁻⁴) and it was: repaglinide(7.15 × 10⁻⁵) ≥ glibenclamide(EC50 = 9.10 × 10⁻⁵) > nateglinide(EC50 = 1.80 × 10⁻⁴) ≥ tolbutamide(EC50 = 2.19 × 10⁻⁴) > glimepiride(EC50=–) inSOL. The drug‐induced atrophy can be explained by theKATPchannel block and by the enhancement of the mitochondrialSDHactivity. In an 8‐month period, muscle atrophy was found in 0.27% of the glibenclamide reports in humans and in 0.022% of the other not sulfonylureas and glinides drugs. No reports of atrophy were found for the other sulfonylureas and glinides in theFDA‐AERS. Glibenclamide induces atrophy in animal experiments and in human patients. Glimepiride shows less potential for inducing atrophy.

Bisphosphonates (BPs) reduce bone pain and fractures by balancing the osteoblast/osteoclast ratio. The behavior of ion channels in the presence of BPs is not known. To investigate this, the effect of zoledronic acid BP (ZOL) (3 × 10⁻⁸ to 5 × 10⁻⁴ M) treatment, on ion channels, cell proliferation, and mineralization, has been investigated on preosteoclast-like cells, RAW264.7, preosteoblast-like cells MC3T3-E1, and rat/mouse native bone marrow-derived osteoblasts. In whole-cell patch clamp on cell line- and bone marrow-derived osteoblasts, ZOL potentiated outward currents. On RAW264.7, ZOL (10⁻⁴ M)-evoked current was reduced by the Kv channel blocker tetraethylammonium hydrochloride (TEA), but not by the selective TRPV1-channel antagonist capsazepine. On MC3T3-E1 cells and bone marrow-derived osteoblasts, ZOL-evoked current (5 × 10⁻⁸ to 10⁻⁴ M) was reduced by capsazepine, whereas the selective TRPV1-channel agonist capsaicin potentiated the control current. In the cell proliferation assay, 72 h incubation of RAW264.7 and MC3T3-E1 cells with ZOL reduced proliferation, with IC₅₀ values of 2.62 × 10⁻⁷ M and 2.02 × 10⁻⁵ M, respectively. Mineralization of MC3T3-E1 cells and bone marrow-derived osteoblasts was observed in the presence of capsaicin and ZOL (5 × 10⁻⁸–10⁻⁷ M); ZOL effects were antagonized by capsazepine. In summary, the ZOL-induced activation of TRPV1 channel mediates the mineralization of osteoblasts and counterbalances the antiproliferative effects, increasing the IC₅₀. This mechanism is not operative in osteoclasts lacking the TRPV1 channel.

Therapeutic monoclonal antibodies (mAbs) have high efficacy in treating TNFα‐related immunological diseases. Other than neutralizing TNFα, these IgG1 antibodies exert Fc receptor‐mediated effector functions such as the complement‐dependent cytotoxicity (CDC) and antibody‐dependent cell cytotoxicity (ADCC). The crystallizable fragment (Fc) of these IgG1 contains a single glycosylation site at Asn 297/300 that is essential for the CDC and ADCC. Glycosylated antibodies lacking core fucosylation showed an improved ADCC. However, no structural data are available concerning the ligand‐binding interaction of these mAbs used in TNFα‐related diseases and the role of the fucosylation. We therefore used comparative modeling for generating complete 3D mAb models that include the antigen‐binding fragment (Fab) portions of infliximab, complexed with TNFα (4G3Y.pdb), the Fc region of the human IGHG1 fucosylated (3SGJ) and afucosylated (3SGK) complexed with the Fc receptor subtype FcγRIIIA, and the Fc region of a murine immunoglobulin (1IGT). After few thousand steps of energy minimization on the resulting 3D mAb models, minimized final models were used to quantify interactions occurring between FcγRIIIA and the fucosylated/afucosylated Fc fragments. While fucosylation does not affect Fab‐TNFα interactions, we found that in the absence of fucosylation the Fc–mAb domain and FcγRIIIA are closer and new strong interactions are established between G129 of the receptor and S301 of the Chimera 2 Fc mAb; new polar interactions are also established between the Chimera 2 Fc residues Y299, N300, and S301 and the FcγRIIIA residues K128, G129, R130, and R155. These data help to explain the reduced ADCC observed in the fucosylated mAbs suggesting the specific AA residues involved in binding interactions.