In the last two decades, there has been a growing interest in unraveling the role that the Na⁺/Ca²⁺ exchanger (NCX) plays in the function and regulation of several cellular activities. Molecular biology, electrophysiology, genetically modified mice, and molecular pharmacology have helped to delve deeper and more successfully into the physiological and pathophysiological role of this exchanger. In fact, this nine-transmembrane protein, widely distributed in the brain and in the heart, works in a bidirectional way. Specifically, when it operates in the forward mode of operation, it couples the extrusion of one Ca²⁺ ion with the influx of three Na⁺ ions. In contrast, when it operates in the reverse mode of operation, while three Na⁺ ions are extruded, one Ca²⁺ enters into the cells. Different isoforms of NCX, named NCX1, NCX2, and NCX3, have been described in the brain, whereas only one, NCX1, has been found in the heart. The hypothesis that NCX can play a relevant role in several pathophysiological conditions, including hypoxia-anoxia, white matter degeneration after spinal cord injury, brain trauma and optical nerve injury, neuronal apoptosis, brain aging, and Alzheimer's disease, stems from the observation that NCX, in parallel with selective ion channels and ATP-dependent pumps, is efficient at maintaining intracellular Ca²⁺ and Na⁺ homeostasis. In conclusion, although studies concerning the involvement of NCX in the pathological mechanisms underlying brain injury during neurodegenerative diseases started later than those related to heart disease, the availability of pharmacological agents able to selectively modulate each NCX subtype activity and antiporter mode of operation will provide a better understanding of its pathophysiological role and, consequently, more promising approaches to treat these neurological disorders.

The role of dopamine agonist treatment in corticotroph pituitary tumors is controversial. The aim of this study was to evaluate D₂ receptor expression in 20 corticotroph pituitary tumors and to correlate it to the in vitro effect of dopamine agonists on ACTH secretion and the in vivo effect of short-term cabergoline treatment on cortisol secretion. D₂ expression was evaluated by receptor-ligand binding, immunohistochemistry, and RT-PCR. A 50% or more decrease in daily urinary cortisol levels was considered a significant clinical response. At receptor-ligand binding, specific binding of [¹²⁵I]epidepride was found in 80% of cases. At immunohistochemistry, specific D₂ immunostaining was found in 75% of cases. D₂ expression was found in 83.3% of cases (D_2long in 40%, D_2short in 20%, and both in 40%) by RT-PCR. Significant in vitro inhibition of ACTH secretion was found in 100% of D₂-positive cases, but not in 100% of D₂-negative cases by either bromocriptine or cabergoline. A significant in vivo inhibition of cortisol secretion after 3-month cabergoline treatment was found in 60%, although a normalization of cortisol secretion was found in 40% of cases. All cabergoline-responsive cases were associated with D₂ expression, whereas all noncabergoline-responsive cases but one were not associated with D₂ expression. In conclusion, functional D₂ receptors were expressed in approximately 80% of corticotroph pituitary tumors. The effectiveness of cabergoline in normalizing cortisol secretion in 40% of cases supports its therapeutic use in the management of Cushing’s disease.

Brain activity during rest is characterized by slow (0.01–0.1 Hz) fluctuations of blood oxygenation level-dependent functional magnetic resonance imaging signals. These fluctuations are organized as functional connectivity networks called resting-state networks, anatomically corresponding to specific neuronal circuits. As Parkinson’s disease is mainly characterized by a dysfunction of the sensorimotor pathways, which can be influenced by levodopa administration, the present study investigated the functional connectivity changes within the sensorimotor resting-state network in drug-naïve patients with Parkinson’s disease after acute levodopa administration. Using a double-blind placebo-controlled design, resting-state functional magnetic resonance imaging was carried out in 20 drug-naïve patients with Parkinson’s disease, immediately before and 60 min after, oral administration of either levodopa or placebo. Control resting-state functional magnetic resonance imaging data were recorded in 18 age- and sex-matched healthy volunteers. Independent component analysis was performed to extract resting-state network maps and associated time-course spectral features. At the anatomical level, levodopa enhanced the sensorimotor network functional connectivity in the supplementary motor area, a region where drug-naïve patients with Parkinson’s disease exhibited reduced signal fluctuations compared with untreated patients. At the spectral frequency level, levodopa stimulated these fluctuations in a selective frequency band of the sensorimotor network. The reported effects induced by levodopa on sensorimotor network topological and spectral features confirm that the sensorimotor system is a target of acute levodopa administration in drug-naïve patients with Parkinson’s disease. Moreover, while the regional changes in supplementary motor area reflect the functional improvement in motor function, the rhythm-specific modulation induced by the dopamine precursor discloses a novel aspect of pharmacological stimulation in Parkinson’s disease, adding further insight to the comprehension of levodopa action.

KCNQ subunits encode for the M current (I_KM), a neuron-specific voltage-dependent K⁺current with a well established role in the control of neuronal excitability. In this study, by means of a combined biochemical, pharmacological, and electrophysiological approach, the role of presynapticI_KMin the release of previously taken up tritiated norepineprine (NE), GABA, andd-aspartate (d-ASP) from hippocampal nerve terminals (synaptosomes) has been evaluated. Retigabine (RT) (0.01-30 μm), a specific activator ofI_KM, inhibited [³H]NE, [³H]d-ASP, and [³H]GABA release evoked by 9 mmextracellular K⁺([K⁺]_e). RT-induced inhibition of [³H]NE release was prevented by synaptosomal entrapment of polyclonal antibodies directed against KCNQ2 subunits, an effect that was abolished by antibody preabsorption with the KCNQ2 immunizing peptide; antibodies against KCNQ3 subunits were ineffective. Flupirtine (FP), a structural analog of RT, also inhibited 9 mm[K⁺]_e-induced [³H]NE release, although its maximal inhibition was lower than that of RT. Electrophysiological studies in KCNQ2-transfected Chinese hamster ovary cells revealed that RT and FP (10 μm) caused a -19 and -9 mV hyperpolarizing shift, respectively, in the voltage dependence of activation of KCNQ2 K⁺channels. In the same cells, the cognition enhancer 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE-991) (10 μm) blocked KCNQ2 channels and prevented their activation by RT (1-10 μm). Finally, both XE-991 (10-100 μm) and tetraethylammonium ions (100 μm) abolished the inhibitory effect of RT (1 μm) on [³H]NE release. These findings provide novel evidence for a major regulatory role of KCNQ2 K⁺channel subunits in neurotransmitter release from rat hippocampal nerve endings.