Neuroinflammation is one of the hallmarks of Parkinson’s disease (PD) and may contribute to midbrain dopamine (DA) neuron degeneration. Recent studies link chronic inflammation with failure to resolve early inflammation, a process operated by specialized pro-resolving mediators, including resolvins. However, the effects of stimulating the resolution of inflammation in PD – to modulate disease progression – still remain unexplored. Here we show that rats overexpressing human α-synuclein (Syn) display altered DA neuron properties, reduced striatal DA outflow and motor deficits prior to nigral degeneration. These early alterations are coupled with microglia activation and perturbations of inflammatory and pro-resolving mediators, namely IFN-γ and resolvin D1 (RvD1). Chronic and early RvD1 administration in Syn rats prevents central and peripheral inflammation, as well as neuronal dysfunction and motor deficits. We also show that endogenous RvD1 is decreased in human patients with early-PD. Our results suggest there is an imbalance between neuroinflammatory and pro-resolving processes in PD.
SARS-CoV-2 variants with concerning characteristics have emerged since the end of 2020. Surveillance of SARS-CoV-2 variants was performed on a total of 4,851 samples from the capital city and 10 provinces of Argentina, during 51 epidemiological weeks (EWs) that covered the end of the first wave and the ongoing second wave of the COVID-19 pandemic in the country (EW 44/2020 to EW 41/2021). The surveillance strategy was mainly based on Sanger sequencing of a Spike coding region that allows the identification of signature mutations associated with variants. In addition, whole-genome sequences were obtained from 637 samples. The main variants found were Gamma and Lambda, and to a lesser extent, Alpha, Zeta, and Epsilon, and more recently, Delta. Whereas, Gamma dominated in different regions of the country, both Gamma and Lambda prevailed in the most populated area, the metropolitan region of Buenos Aires. The lineages that circulated on the first wave were replaced by emergent variants in a term of a few weeks. At the end of the ongoing second wave, Delta began to be detected, replacing Gamma and Lambda. This scenario is consistent with the Latin American variant landscape, so far characterized by a concurrent increase in Delta circulation and a stabilization in the number of cases. The cost-effective surveillance protocol presented here allowed for a rapid response in a resource-limited setting, added information on the expansion of Lambda in South America, and contributed to the implementation of public health measures to control the disease spread in Argentina.
A BS TRACT: Background: In experimental models of Parkinson's disease (PD), different degrees of degeneration to the nigrostriatal pathway produce distinct profiles of synaptic alterations that depend on progressive changes in N-methyl-D-aspartate receptors (NMDAR)-mediated functions. Repetitive transcranial magnetic stimulation (rTMS) induces modifications in glutamatergic and dopaminergic systems, suggesting that it may have an impact on glutamatergic synapses modulated by dopamine neurotransmission. However, no studies have so far explored the mechanisms of rTMS effects at early stages of PD. Objectives: We tested the hypothesis that in vivo application of rTMS with intermittent theta-burst stimulation (iTBS) pattern alleviates corticostriatal dysfunctions by modulating NMDAR-dependent plasticity in a rat model of early parkinsonism. Methods: Dorsolateral striatal spiny projection neurons (SPNs) activity was studied through ex vivo whole-cell patch-clamp recordings in corticostriatal slices obtained from 6-hydroxydopamine-lesioned rats, subjected to a single session (acute) of iTBS and tested for forelimb akinesia with the stepping test. Immunohistochemical analyses were performed to analyze morphological correlates of plasticity in SPNs. Results: Acute iTBS ameliorated limb akinesia and rescued corticostriatal long-term potentiation (LTP) in SPNs of partially lesioned rats. This effect was abolished by applying a selective inhibitor of GluN2B-subunit-containing NMDAR, suggesting that iTBS treatment could be associated with an enhanced activation of specific NMDAR subunits, which are major regulators of structural plasticity during synapse development. Morphological analyses of SPNs revealed that iTBS treatment reverted dendritic spine loss inducing a prevalence of thin-elongated spines in the biocytin-filled SPNs. Conclusions: Taken together, our data identify that an acute iTBS treatment produces a series of plastic changes underlying striatal compensatory adaptation in the parkinsonian basal ganglia circuit.
Levodopa (L-DOPA) treatment is the main gold-standard therapy for Parkinson disease (PD). Besides good antiparkinsonian effects, prolonged use of this drug is associated to the development of involuntary movements known as L-DOPA-induced dyskinesia (LID). L-DOPA-induced dyskinesia is linked to a sensitization of dopamine (DA) D1 receptors located on spiny projection neurons (SPNs) of the dorsal striatum. Several evidences have shown that the emergence of LID can be related to striatal D1/cAMP/PKA/DARPP-32 and extracellular signal-regulated kinases (ERK1/2) pathway overactivation associated to aberrant N-methyl-d-aspartate (NMDA) receptor function. In addition, within striatum, ERK1/2 is also able to modulate in a D1 receptor-dependent manner the activity of the mammalian target of rapamycin complex 1 (mTORC1) pathway under DA depletion and L-DOPA therapy. Consistently, increased mTORC1 signaling appears during chronic administration of L-DOPA and shows a high correlation with the severity of dyskinesia. Furthermore, the abnormal activation of the D1/PKA/DARPP-32 cascade is paralleled by increased phosphorylation of the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor at the PKA Ser845 site. The GluA1 promotes excitatory AMPA receptor-mediated transmission and may be implicated in the alterations found at the corticostriatal synapses of dyskinetic animals. In our study, we investigated the role of mTORC1 pathway activation in modulating bidirectional striatal synaptic plasticity in L-DOPA-treated parkinsonian rats. Inhibition of mTORC1 by coadministration of rapamycin to L-DOPA was able to limit the magnitude of LID expression, accounting for a therapeutic effect of this
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