Background: Diuretics, have been accepted as first-line treatment in refractory heart failure, but a lack of response is a frequent event. A randomised single blind study was performed to evaluate the effects of the combination of high-dose Ž . furosemide and small-volume hypertonic saline solution HSS infusion in the treatment of refractory NYHA class IV Ž . Ž . Ž . congestive heart failure CHF . Materials and methods: Sixty patients 21 Fr39 M with refractory CHF NYHA class IV of different etiologies, unresponsive to high oral doses of furosemide, ACE-inhibitors, digitalis, and nitrates, aged 65᎐90 years, Ž . were enrolled. They had to have an ejection fraction EF -35%, serum creatinine -2 mgrdl, BUN F 60 mgrdl, a reduced Ž . Ž . urinary volume and a low natriuresis. The patients were randomised in two groups single blind : group 1 11 Fr19 M Ž . Ž . Ž received an i.v. infusion of furosemide 500᎐1000 mg plus HSS 150 ml of 1.4᎐4.6% NaCl b.i.d. in 30 min. Group 2 10 Fr20 . Ž . M received an i.v. bolus of furosemide 500᎐1000 mg b.i.d., without HSS, during a period lasting 6᎐12 days. Both groups Ž . received KCl 20᎐40 mEq. i.v. to prevent hypokalemia. All patients underwent at entry a physical examination, measurement Ž . Ž . Ž . of body weight BW , blood pressure BP , heart rate HR , evaluation of signs of CHF, and controls of serum Na, K, Cl, bicarbonate, albumin, uric acid, creatinine, urea and glycemia and daily during hospitalization, as well as the daily output of urine for, Na, K and Cl measurements. Chest X-ray, ECG and echocardiogram were obtained at entry during and at the discharge. During the treatment and after discharge the daily dietary Na intake was 120 mmol with a drink fluid intake of 1000 ml daily. An assessment of BW and 24-h urinary volume, serum and urinary laboratory parameters, until reaching a Ž . compensated state, were performed daily, when i.v. furosemide was replaced with oral administration 250᎐500 mgrday . After discharge, patients were followed as outpatients weekly for the first 3 months and subsequently once per month. Results: The groups were similar for age, sex, EF, risk factors, treatment and etiology of CHF. All patients showed a clinical improvement. Ž . Six patients in both groups had hyponatremia from 120 to 128 mEq.rl at entry. A significant increase in daily diuresis in both Ž . Ž groups was observed from 390 " 155 to 2100 " 626, and from 433 " 141 to 1650 " 537 mlr24 h, P -0.05 . Natriuresis from . Ž . 49 " 15 to 198 " 28 mEq.r24 h was higher in group 1 vs. group 2 from 53.83" 12 to 129 " 39 mEq.r24 h, P -0.05 . Serum Ž . Ž Na from 135.9" 6.8 to 142.2" 3.8 mEq.rl, P-0.05 increased in the group 1 and decreased in the group 2 from 134.7" 7.9. Ž . to 130.1" 4.3 mEq.rl . Serum K was decreased from 4.4" 0.6 to 3.9" 0.6, and 4.6" 9 to 3.6" 0.5 mEq.rl, P-0. 05 in both Ž . groups. BW was reduced from 73.8" 9.1 to 63.8" 8.8, and from 72.9" 10.2 to 64.5" 7.5 kg, P-0. 05 in both groups. Group Ž . 2 showed more patients in NYHA class III than group 1 18 vs. 2 patients, P -0.0...
Misfolding and aggregation of α-synuclein are specific features of Parkinson’s disease and other neurodegenerative diseases defined as synucleinopathies. Parkinson’s disease progression has been correlated with the formation and the extracellular release of α-synuclein aggregates, as well as with their spreading from neuron to neuron. Therapeutic interventions in the initial stages of Parkinson’s disease require a clear understanding of the mechanisms by which α-synuclein disrupts the physiological synaptic and plastic activity of the basal ganglia. For this reason, here we have identified two early time points to clarify how the intrastriatal injection of α-synuclein preformed fibrils in rodents, via retrograde transmission, induces time-dependent electrophysiological and behavioral alterations. We found that intrastriatal α-synuclein preformed fibrils perturb the firing rate of dopaminergic neurons of the substantia nigra pars compacta while the discharge of putative GABAergic cells of the substantia nigra pars reticulata is unchanged. The α-synuclein-induced dysregulation of nigrostriatal function also impairs, in a time-dependent manner, the two main forms of striatal synaptic plasticity, long-term potentiation and long-term depression. We also observed an increased glutamatergic transmission measured as an augmented frequency of spontaneous excitatory synaptic currents. These changes in neuronal function in the substantia nigra pars compacta and striatum were observed before overt neuronal death occurred. In an additional set of experiments, we were able to rescue α-synuclein-induced alterations of motor function, striatal synaptic plasticity, and increased spontaneous excitatory synaptic currents by a sub-chronic treatment with L-Dopa, a precursor of dopamine widely used in the therapy of Parkinson’s disease, clearly demonstrating that a dysfunctional dopamine system plays a critical role in the early phases of the disease.
Poly (ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that is involved in physiological processes as DNA repair, genomic stability, and apoptosis. Moreover, published studies demonstrated that PARP-1 mediates necrotic cell death in response to excessive DNA damage under certain pathological conditions. In Huntington’s disease brains, PARP immunoreactivity was described in neurons and in glial cells, thereby suggesting the involvement of apoptosis in HD. In this study, we sought to determine if the PARP-1 inhibitor exerts a neuroprotective effect in R6/2 mutant mice, which recapitulates, in many aspects, human HD. Transgenic mice were treated with the PARP-1 inhibitor INO-1001 mg/Kg daily starting from 4 weeks of age. After transcardial perfusion, histological and immunohistochemical studies were performed. We found that INO 1001-treated R6/2 mice survived longer and displayed less severe signs of neurological dysfunction than the vehicle treated ones. Primary outcome measures such as striatal atrophy, morphology of striatal neurons, neuronal intranuclear inclusions and microglial reaction confirmed a neuroprotective effect of the compound. INO-1001 was effective in significantly increasing activated CREB and BDNF in the striatal spiny neurons, which might account for the beneficial effects observed in this model. Our findings show that PARP-1 inhibition could be considered as a valid therapeutic approach for HD.
Parkinson’s disease (PD) is considered the most common disorder of synucleinopathy, which is characterised by intracellular inclusions of aggregated and misfolded α-synuclein (α-syn) protein in various brain regions, and the loss of dopaminergic neurons. During the early prodromal phase of PD, synaptic alterations happen before cell death, which is linked to the synaptic accumulation of toxic α-syn specifically in the presynaptic terminals, affecting neurotransmitter release. The oligomers and protofibrils of α-syn are the most toxic species, and their overexpression impairs the distribution and activation of synaptic proteins, such as the SNARE complex, preventing neurotransmitter exocytosis and neuronal synaptic communication. In the last few years, the role of the immune system in PD has been increasingly considered. Microglial and astrocyte activation, the gene expression of proinflammatory factors, and the infiltration of immune cells from the periphery to the central nervous system (CNS) represent the main features of the inflammatory response. One of the actors of these processes is α-syn accumulation. In light of this, here, we provide a systematic review of PD-related α-syn and inflammation inter-players.
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