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TPC2-A1-N and TPC2-A1-P, two novel small molecules, differentially activate two-pore channel 2 (TPC2) and mimic the activation of TPC2 with NAADP and PIP2, resulting in distinct ion channel selectivities. These two different modes of TPC2 activity have physiological, and possibly pathophysiological, implications as they can modulate vesicle trafficking and lysosomal exocytosis.

T-type calcium channels are involved in the pathophysiology of epilepsy, pain, and sleep. Recently, we developed a novel spiroimidazopyridine compound, SAK3 (ethyl 8′-methyl-2′,4-dioxo-2-(piperidin-1-yl)-2′H-spiro[cyclopentane-1,3′-imidazo[1,2-a]pyridine]-2-ene-3-carboxylate), which enhances T-type calcium channel currents and improves memory deficits in olfactory bulbectomized (OBX) mice. Here, we demonstrated the anti-depressant effects of SAK3 in OBX mice. Chronic SAK3 administration (0.5 or 1.0 mg/kg, p.o.) improved depressive-like behaviors in OBX mice. The impaired adult neurogenesis in the hippocampal dentate gyrus (DG) that occurred 4 weeks after OBX administration was significantly restored by chronic SAK3 administration (0.5 or 1.0 mg/kg, p.o.). Additionally, SAK3 (0.5 mg/kg, p.o.) promoted the proliferation and survival of newborn cells in the naïve DG. Moreover, SAK3 administration (0.5 mg/kg, p.o.) antagonized the reduction of calcium/calmodulin-dependent protein kinase II (CaMKII) and CaMKIV phosphorylation levels, thereby rescuing the decreased levels of cAMP response element-binding protein (CREB)/brain derived neurotrophic factor (BDNF) signaling in the OBX DG. The effects of SAK3 were completely blocked by the T-type calcium channel selective blocker NNC 55-0396 (12.5 mg/kg, i.p.). Altogether, these results suggest that SAK3 improves depressive-like behaviors by promoting adult neurogenesis via T-type calcium channel stimulation in the hippocampus. Keywords: SAK3, T-type calcium channel, Neurogenesis, Anti-depressant, BDNF

Status epilepticus (SE) is a life-threatening emergency that can cause neurodegeneration with debilitating neurological disorders. However, the mechanism by which convulsive SE results in neurodegeneration is not fully understood. It has been shown that epileptic seizures produce markedly increased levels of nitric oxide (NO) in the brain, and that NO induces Ca2 + release from the endoplasmic reticulum via the type 1 ryanodine receptor (RyR1), which occurs through S-nitrosylation of the intracellular Ca2 + release channel. Here, we show that through genetic silencing of NO-induced activation of the RyR1 intracellular Ca2 + release channel, neurons were rescued from seizure-dependent cell death. Furthermore, dantrolene, an inhibitor of RyR1, was protective against neurodegeneration caused by SE. These results demonstrate that NO-induced Ca2 + release via RyR is involved in SE-induced neurodegeneration, and provide a rationale for the use of RyR1 inhibitors for the prevention of brain damage following SE., Highlights • NO-induced activation of RyR1 is critical for seizure-induced neuronal cell death. • Dantrolene is protective against neurodegeneration caused by epileptic seizures. • RyR1 is a therapeutic candidate to ameliorate the brain damage following seizures. Status epilepticus (SE) is a life-threatening condition that can cause neurodegeneration. Mikami et al. report that NO-induced activation of type 1 ryanodine receptors (RyR1) is involved in SE-induced neuron death. Furthermore, dantrolene, an inhibitor of RyR1, has been found to be protective against neurodegeneration caused by SE.

The influence of direct single pulse and subtetanic electrical stimulation (ES) on isolated rat hemidiaphragm response to adrenoceptor antagonists and calcium channel blockers was investigated. Muscle contractility was stimulated by cumulative micromolar noradrenaline. Noradrenaline effects on developed tension (Td) in the presence of various α- and β-adrenoceptor antagonists (e.g., prazosin and ICI 118551) were qualitatively different during different types of ES. Also, intact L-voltage calcium channels were necessary for noradrenaline-induced potentiation of Td during both types of ES, while the balance between ryanodine receptors- and inositol triphosphate (IP3)-related calcium events in the muscle was influenced by the pattern of the ES. Keywords:: adrenoceptor antagonist, calcium channel blocker, electrical stimulation

Gaucher disease is an inherited metabolic disorder caused by defective activity of the lysosomal enzyme, glucocerebrosidase, resulting in accumulation of the lipids, glucosylceramide (GlcCer), and glucosylsphingosine (GlcSph). Little is known about the mechanism leading from lipid accumulation to disease, particularly in the acute and subacute neuronopathic forms of Gaucher disease, types 2 and 3, respectively. Recent work from our laboratory has shown, in animal models, that GlcCer enhances agonist-induced calcium release from intracellular stores via the ryanodine receptor, which results in neuronal cell death. We now test whether calcium release is altered in human brain tissue obtained post-mortem from Gaucher disease patients. Agonist-induced calcium release via the ryanodine receptor was significantly enhanced (P0.05) in brain microsomes from the acute neuronopathic form of Gaucher disease (type 2) (43 +/- 6% of the calcium in microsomes) compared to the subacute (type 3) (27 +/- 3%) and the non-neuronopathic (type 1) (28 +/- 6%) forms, and controls (18 +/- 3%), and correlated with levels of GlcCer accumulation. These findings suggest that defective calcium homeostasis may be a mechanism responsible for neuropathophysiology in acute neuronopathic Gaucher disease, and may potentially offer new therapeutic approaches for disease management.

Background: To investigate the protective effect of 2-aminoethyl diphenylborinate (2-APB) against ischemia-reperfusion (I/R) injury in the rat kidney by an experimental study. Materials and methods: Thirty male Sprague-Dawley rats were randomly divided into the following three groups: (1) sham group, (2) I/R group, and (3) I/R + 2-APB group. Renal I/ R injury was induced by clamping the left renal pedicle for 45 min after right nephrectomy, followed by 3 h of reperfusion. The therapeutic agent 2-APB was administered intravenously at a dose of 2 mg/kg 10 min before renal ischemia. Glutathione, superoxide dismutase, total antioxidant capacity, malondialdehyde, tumor necrosis factor a, interleukin 6, aspartate aminotransferase, alanine aminotransferase, and creatinine levels were measured from blood samples, and the rats were sacrificed subsequently. Tissue samples were scored histopathologically. Visualization of apoptotic cells was performed using the terminal deoxynucleotidyl transferase dUTP nick end labeling staining method. Results: 2-APB significantly reduced serum malondialdehyde, tumor necrosis factor a, interleukin 6, aspartate aminotransferase, alanine aminotransferase, and creatinine levels in the I/R injury group. However, glutathione, superoxide dismutase, and total antioxidant capacity levels increased significantly. Histopathologic scores were significantly better and the rate of apoptosis was lower in the 2-APB group. Conclusions: 2-APB reduces oxidative stress and damage caused by renal I/R injury. The results of this study demonstrate that 2-APB can be used as an effective agent against I/R injury in the kidney.

Crotoxin (CTX), the major component of the venom from the South American rattlesnake (Crotalus durissus terrificus) has diverse toxic effects, including pre-synaptic neurotoxicity. Among these, the effect of CTX in the heart is the least understood. In this study, we explored the effect(s) of CTX on the electrophysiological activity of neonatal rat cardiomyocytes (NRCM). By using patch, voltage-, and current-clamping techniques, we found that, in NRCM, CTX strongly potentiates L-type Ca2+ currents, an important contributor to the cardiac action potential (AP) and excitation-contraction (EC) coupling. External addition of CTX produced a rapid increase in L-type Ca2+ currents. Addition of verapamil (10 μM) an L-type Ca2+ channel blocker, completely blocked the CTX-induced increase in the currents. A detailed kinetic analysis of AP in NRCM revealed that CTX caused both an elongation of AP duration (APD) and an increase of its amplitude, while a decrease of firing frequency. In addition, increasing concentrations of CTX completely blocked the AP as well as the beating of NRCM. The data indicate that CTX is a potent modulator of L-type Ca2+ currents, which provides a possible mechanistic correlation for the cardiotoxicity of the toxin, and may offer potential clinical implications in the control of cardiac function. Fil: Zhang, Peng. Harvard Medical School; Estados Unidos Fil: Lader, Alan S.. Harvard Medical School; Estados Unidos Fil: Etcheverry, Martin A.. Ventech Research; Estados Unidos Fil: Cantiello, Horacio Fabio. Harvard Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas (i); Argentina

We report induction of TNF-α via the calcium/calcineurin/NFAT pathway in PC12 neural cells. In PC12, expression of TNF-α mRNA, protein and TNF-α gene promoter activity was induced by co-stimulation with phorbol ester and either calcium ionophore A23187 or the L-type Voltage Gated Calcium Channel agonist Bay K 8644. Pre-treatment with calcineurin inhibitors CsA or FK506 inhibited the dominant calcium-dependent component of this induction, limiting it to the level achieved with phorbol ester alone. Promoter activation by Bay was abolished by nifedipine, a specific inhibitor of L-type Voltage Gated Calcium Channels. Exogenous NFAT protein transactivated the TNF-α promoter, and the peptide VIVIT-a specific inhibitor of calcineurin/NFAT binding-blocked calcium-inducible transactivation of the TNF-α promoter. Given proposed functions of TNF-α in spatial learning, memory and the pathogenesis of neurodegenerative diseases, the data presented suggest an important role for calcineurin/NFAT signaling in these key neurological processes. © 2006 Elsevier Inc. All rights reserved., This work was supported by grant 08.5/0039.1/2003 from the Comunidad Autónoma de Madrid (CAM) to E. Cano and by grants to J.M. Redondo from the Ministerio de Ciencia y Tecnología (SAF 2003-02920), the RECAVA programme of the Ministerio de Sanidad y Consumo, the European Union LSHM-CT-2004-005033 (EICOSANOX) and the Fundación La Marato (TV3). A. Canellada was supported by a fellowship from the Ministerio de Educación y Ciencia and the Fundación Carolina of Spain. E. Cano is a recipient of a Ramon y Cajal contract from the Ministerio de Educación y Ciencia.