siRNA lipid nanoparticles for CXCL12 silencing modulate brain immune response during Zika infection.

CXCL12 is a key chemokine implicated in neuroinflammation, particularly during Zika virus (ZIKV) infection. Specifically, CXCL12 is upregulated in circulating cells of ZIKV infected patients. Here, we developed a lipid nanoparticle (LNP) to deliver siRNA in vivo to assess the impact of CXCL12 silencing in the context of ZIKV infection. The biodistribution of the LNP was assessed in vivo after intravenous injection using fluorescently tagged siRNA. Next, we investigated the ability of the developed LNP to silence CXCL12 in vivo and assessed the resulting effects in a murine model of ZIKV infection. The LNP encapsulating siRNA significantly inhibited CXCL12 levels in the spleen and induced microglial activation in the brain during ZIKV infection. This activation was evidenced by the enhanced expression of iNOS, TNF-α, and CD206 within microglial cells. Moreover, T cell subsets exhibited reduced secretion of IFN-É£ and IL-17 following LNP treatment. Despite no observable alteration in viral load, CXCL12 silencing led to a significant reduction in type-I interferon production compared to both ZIKV-infected and uninfected groups. Furthermore, we found grip strength deficits in the group treated with siRNA-LNP compared to the other groups. Our data suggest a correlation between the upregulated pro-inflammatory cytokines and the observed decrease in strength. Collectively, our results provide evidence that CXCL12 silencing exerts a regulatory influence on the immune response in the brain during ZIKV infection. In addition, the modulation of T-cell activation following CXCL12 silencing provides valuable insights into potential protective mechanisms against ZIKV, offering novel perspectives for combating this infection.

SARS-CoV-2 and Hypertension: Evidence Supporting Invasion into the Brain Via Baroreflex Circuitry and the Role of Imbalanced Renin-Angiotensin-Aldosterone-System.

Hypertension is considered one of the most critical risk factors for COVID-19. Evidence suggests that SARS-CoV-2 infection produces intense effects on the cardiovascular system by weakening the wall of large vessels via vasa-vasorum. In this commentary, we propose that SARS-CoV-2 invades carotid and aortic baroreceptors, leading to infection of the nucleus tractus solitari (NTS) and paraventricular hypothalamic nucleus (PVN), and such dysregulation of NTS and PVN following infection causes blood pressure alteration at the central level. We additionally explored the hypothesis that SARS-CoV-2 favors the internalization of membrane ACE2 receptors generating an imbalance of the renin-angiotensin-aldosterone system (RAAS), increasing the activity of angiotensin II (ANG-II), disintegrin, and metalloproteinase 17 domain (ADAM17/TACE), eventually modulating the integration of afferents reaching the NTS from baroreceptors and promoting increased blood pressure. These mechanisms are related to the increased sympathetic activity, which leads to transient or permanent hypertension associated with SARS-CoV-2 invasion, contributing to the high number of deaths by cardiovascular implications.

Acute exercise increases BDNF serum levels in patients with Parkinson's disease regardless of depression or fatigue.

Studies have consistently reported a decreased level of brain-derived neurotrophic factor (BDNF) in individuals with Parkinson's disease (PD). The benefits of exercise on BDNF levels are well-documented in humans, however, the effects of acute exercise are inconclusive in neurological disorders. In addition, there are no studies investigating a precursor molecule - proBDNF - and its comparison to patients with vs. without depression or fatigue. Thirty patients with PD were instructed to walk on a treadmill at light to moderate intensity for 30 min. Generalized Estimating Equation (GEE) showed a significant effect of time (pre- vs. post-exercise) when compared individuals with vs. without depression [Wald Chi Square (4.392), p = 0.036)] and with vs. without fatigue [Wald Chi Square (7.123), p = 0.008)] for mature BDNF (mBDNF) level. There was no effect of group, time, and group x time interaction for proBDNF level when compared individuals with vs. without depression or fatigue. The present study showed that a single bout of light to moderate-intensity exercise increases mBDNF serum levels in patients with PD regardless of depression and fatigue. Our finding is important because it is necessary investigate methods to enhance the gains made by rehabilitation, especially when considering a short period of rehabilitation in different health services. The increase in mBDNF level can lead to an enhancement of neuroplasticity and facilitate the improvement of motor performance. No effect on proBDNF level could be explained, as this precursor molecule is cleaved by intracellular or extracellular enzymes.

Multimodal early-life stress induces biological changes associated to psychopathologies.

Evidences suggest the contributive role of early-life stress (ELS) to affective and anxiety disorders. Chronic exposure to the same stressor may generate habituation, while the exposure to different and repeated stressors gradually promotes maladaptive plasticity. Therefore, to further understand the effects of heterotypic stressors during early life period, male Wistar rat pups (P1-P21) were exposed to Multimodal ELS paradigm. Results indicate pups did not habituate to multimodal ELS and neonates respond to both physical and psychogenic stressors. Adult rats that underwent ELS protocol showed significant lower sucrose intake, decreased latency to immobility in the forced swim test and increased latency to light compartment in the light-dark test when compared to control group. Although it has been shown that ELS-induced changes in hippocampus can be used as biomarkers, multimodal ELS did not significantly alter BDNF, Tyrosine Kinase B (TrkB) receptor expression or neurogenesis in the hippocampus. Taken together, these findings indicate that multimodal ELS protocol can be an interesting experimental model for understanding long-term psychiatric disorders associated with stress. Indeed, our data with neurogenesis, BDNF and TrkB, and conflicting data from the literature, suggest that additional studies on synaptic plasticity/intracellular cascades would help to detect the underlying mechanisms.

Intense olfactory stimulation blocks seizures in an experimental model of epilepsy.

There are reports of patients whose epileptic seizures are prevented by means of olfactory stimulation. Similar findings were described in animal models of epilepsy, such as the electrical kindling of amygdala, where olfactory stimulation with toluene (TOL) suppressed seizures in most rats, even when the stimuli were 20% above the threshold to evoke seizures in already kindled animals. The Wistar Audiogenic Rat (WAR) strain is a model of tonic-clonic seizures induced by acute acoustic stimulation, although it also expresses limbic seizures when repeated acoustic stimulation occurs - a process known as audiogenic kindling (AK). The aim of this study was to evaluate whether or not the olfactory stimulation with TOL would interfere on the behavioral expression of brainstem (acute) and limbic (chronic) seizures in the WAR strain. For this, animals were exposed to TOL or saline (SAL) and subsequently exposed to acoustic stimulation in two conditions that generated: I) acute audiogenic seizures (only one acoustic stimulus, without previous seizure experience before of the odor test) and II) after AK (20 acoustic stimuli [2 daily] before of the protocol test). We observed a decrease in the seizure severity index of animals exposed only to TOL in both conditions, with TOL presented 20s before the acoustic stimulation in both protocols. These findings were confirmed by behavioral sequential analysis (neuroethology), which clearly indicated an exacerbation of clusters of specific behaviors such as exploration and grooming (self-cleaning), as well as significant decrease in the expression of brainstem and limbic seizures in response to TOL. Thus, these data demonstrate that TOL, a strong olfactory stimulus, has anticonvulsant properties, detected by the decrease of acute and AK seizures in WARs.

Influências do Ambiente Sobre a Susceptibilidade às Crises Epilépticas: As Lições dos Modelos Experimentais / Environment influence over epileptic seizure susceptibility: the lessons from experimental models

O propósito principal desta revisão é discutir a influência do ambiente sobre a susceptibilidade a crises e a epilepsia. Nós estamos constantemente expostos a diversas condições que exercem influências, positivas e negativas, sobre a nossa qualidade de vida. Esses fatores externos são capazes de moldar nossos cérebros desde a vida intrauterina até a morte. Eventos estressantes são reconhecidos como fator desencadeador de crises em pacientes com epilepsia. Diversos estudos experimentais estão de acordo com esses achados clínicos e apontam a corticosterona como o principal fator pró-convulsivo. Entretanto, os dados experimentais são vastos e apenas com atenção podemos detectar as informações relevantes. Por outro lado, ambientes enriquecidos promovem alterações plásticas em nossos cérebros, particularmente através da neurogênese, e podem potencialmente reduzir a susceptibilidade a crises, o dano neuronal e a neurogênese anormal induzidos pelas próprias crises. Finalmente, a prática regular de exercício físico tem se mostrado capaz de reduzir a frequência de crises e retardar o processo epileptogênico em modelos animais de epilepsia, além de reduzir ou mesmo eliminar os efeitos do estresse.

The main purpose of this review is to bring out to discussion the environment influence over seizure susceptibility and epilepsy. We are constantly exposed to such different conditions that exert positive as well as negative influences in our quality of life. These external factors are able to shape our brains and neural circuits from intrauterine life until death. Stressful events are known as seizure precipitants in patients with epilepsy. Although several animal studies are in line with these clinical findings, pointing out that corticosterone is one of the major pro-convulsant factor, however the experimental data are vast and only with close attention we can detect the relevant information. On the other hand, enriched environments promote plastic changes in our brains, particularly through neurogenesis, that can potentially reduce seizure susceptibility, and the aberrant neurogenesis and neuronal damage both induced by the seizures themselves. Finally, regular practice of physical exercise has been shown to reduce seizure frequency and delay epileptogenic process in animal models of epilepsy, in addition to reduce, or even eliminate stress levels.