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Background Systemic bacterial infections often result in enduring cognitive impairment and are a risk factor for dementia. There are currently no effective treatments for infection-induced cognitive impairment. Previous studies have shown that intermittent fasting (IF) can increase the resistance of neurons to injury and disease by stimulating adaptive cellular stress responses. However, the impact of IF on the cognitive sequelae of systemic and brain inflammation is unknown. Methods Rats on IF for 30 days received 1 mg/kg of lipopolysaccharide (LPS) or saline intravenously. Half of the rats were subjected to behavioral tests and the other half were euthanized two hours after LPS administration and the hippocampus was dissected and frozen for analyses. Results Here, we report that IF ameliorates cognitive deficits in a rat model of sepsis by a mechanism involving NF-κB activation, suppression of the expression of pro-inflammatory cytokines, and enhancement of neurotrophic support. Treatment of rats with LPS resulted in deficits in cognitive performance in the Barnes maze and inhibitory avoidance tests, without changing locomotor activity, that were ameliorated in rats that had been maintained on the IF diet. IF also resulted in reduced levels of mRNAs encoding the LPS receptor TLR4 and inducible nitric oxide synthase (iNOS) in the hippocampus. Moreover, IF prevented LPS-induced elevation of IL-1α, IL-1β and TNF-α levels, and prevented the LPS-induced reduction of BDNF levels in the hippocampus. IF also significantly attenuated LPS-induced elevations of serum IL-1β, IFN-γ, RANTES, TNF-α and IL-6 levels. Conclusions Taken together, our results suggest that IF induces adaptive responses in the brain and periphery that can suppress inflammation and preserve cognitive function in an animal model of systemic bacterial infection.

Ouabain (OUA) is a cardiac glycoside that binds to Na + ,K + -ATPase (NKA), a conserved membrane protein that controls cell transmembrane ionic concentrations and requires ATP hydrolysis. At nM concentrations, OUA activates signaling pathways that are not related to its typical inhibitory effect on the NKA pump. Activation of these signaling pathways protects against some types of injury of the kidneys and central nervous system. There are 4 isoforms of the alpha subunit of NKA, which are differentially distributed across tissues and may have different physiological roles. Glial cells are important regulators of injury and inflammation in the brain and express the α1 and α2 NKA isoforms. This study investigated the role of α2 NKA in OUA modulation of the neuroinflammatory response induced by lipopolysaccharide (LPS) in mouse primary glial cell cultures. LPS treatment increased lactate dehydrogenase release, while OUA did not decrease cell viability and blocked LPS-induced NF-κB activation. Silencing α2 NKA prevented ERK and NF-κB activation by LPS. α2 NKA also regulates TNF-α and IL-1β levels. The data reported here indicate a significant role of α2 NKA in regulating central LPS effects, with implications in the associated neuroinflammatory processes.

Neuroinflammation, often driven by the overproduction of reactive oxygen species (ROS), plays a crucial role in the pathogenesis of neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. The susceptibility of the brain to oxidative stress is attributed to its high metabolic activity and limited antioxidant defense. This study aimed to evaluate the neuroprotective potential of Benzylidene Digoxin 15 (BD-15) following treatment and pretreatment in a lipopolysaccharide (LPS)-induced neuroinflammation model. Additionally, we examined whether BD-15 enhances the generation of neurons from neural progenitor cells (NPCs).Male Wistar rats were used for acute treatment studies and divided into four groups: control (saline), BD-15 (100 μg/kg), LPS (250 μg/kg), and LPS + BD-15 (250 μg/kg + 100 μg/kg). Swiss albino mice were used for chronic pretreatment studies and divided into the following groups: control (saline), BD-15 (0.56 mg/kg), LPS (1 mg/kg), and LPS + BD-15 (1 mg/kg + 0.56 mg/kg). Behavioral changes were assessed using the open field test, and brain tissues were analyzed for oxidative stress markers, including malondialdehyde (MDA), reduced glutathione (GSH), protein carbonylation, catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST). To assess neurogenesis, primary NPC cultures derived from the hippocampus of newborn Wistar rats were used, which led to reduced locomotor activity and increased oxidative stress, particularly in the cortex, as indicated by elevated MDA levels and reduced GSH levels. BD-15 treatment reversed these effects, notably by restoring GSH levels and reducing protein carbonylation in the cerebellum. Chronic BD-15 treatment in Swiss mice improved oxidative stress markers including MDA, SOD, CAT, and GST. Furthermore, BD-15 exhibits neuroprotective properties by alleviating oxidative stress and motor dysfunction, suggesting its potential as a therapeutic agent for neuroinflammatory disorders. However, BD-15 did not affect NPC cell proliferation, indicating that this cardiotonic steroid did not alter the cell cycle of these progenitor cells.

The Sonic hedgehog (Shh) signaling pathway is well known in patterning of the neural tube during embryonic development, but its emerging role in differentiated neurons is less understood. Here we report that Shh enhances autophagy in cultured hippocampal neurons. Microarray analysis reveals the upregulation of multiple autophagy-related genes in neurons in response to Shh application. Through analysis of the autophagy-marker LC3 by immunoblot analysis and immunocytochemistry, we confirm activation of the autophagy pathway in Shh-exposed neurons. Using electron microscopy, we find autophagosomes and associated structures with a wide range of morphologies in synaptic terminals of Shh-exposed neurons. Moreover, we show that Shh-triggered autophagy depends on class III Phosphatidylinositol 3-kinase complexes (PtdIns3K). These results identify a link between Shh and autophagy pathways and, importantly, provide a lead for further understanding the physiology of Shh signaling activity in neurons.

Cocaine is a worldwide used drug and its abuse is associated with physical, psychiatric and social problems. The mechanism by which cocaine causes neurological damage is very complex and involves several neurotransmitter systems. For example, cocaine increases extracellular levels of dopamine and free radicals, and modulates several transcription factors. NF-κB is a transcription factor that regulates gene expression involved in cellular death. Our aim was to investigate the toxicity and modulation of NF-κB activity by cocaine in PC 12 cells. Treatment with cocaine (1 mM) for 24 hours induced DNA fragmentation, cellular membrane rupture and reduction of mitochondrial activity. A decrease in Bcl-2 protein and mRNA levels, and an increase in caspase 3 activity and cleavage were also observed. In addition, cocaine (after 6 hours treatment) activated the p50/p65 subunit of NF-κB complex and the pretreatment of the cells with SCH 23390, a D1 receptor antagonist, attenuated the NF-κB activation. Inhibition of NF-κB activity by using PDTC and Sodium Salicilate increased cell death caused by cocaine. These results suggest that cocaine induces cell death (apoptosis and necrosis) and activates NF-κB in PC12 cells. This activation occurs, at least partially, due to activation of D1 receptors and seems to have an anti-apoptotic effect on these cells.

Diabetes-induced vascular dysfunction has mainly been studied in males. However, the mechanisms involved may not correspond to those in females. Here we analyzed the effects of tetrahydrobiopterin (BH 4 ) and chronic insulin on the physiology of mesenteric arterioles of alloxan-diabetic female rats. The parameters studied were the mesenteric arteriolar reactivity (intravital microscopy), nitric oxide synthase (NOS) activity (conversion of L-arginine to L-citrulline), eNOS gene expression (RT-PCR), NO production (diaminofluorescein), reactive oxygen species (ROS) generation (intravital fluorescence microscopy) and Cu/Zn superoxide dismutase (SOD) activity (spectrophotometry) and gene expression (RT-PCR). The reduced endothelium-dependent vasodilation of diabetic females was corrected by both BH 4 and insulin. NOS activity was decreased by diabetes, but insulin did not correct it. However, NOS expression was not modified by either diabetes or insulin. Arterioles of diabetic rats exhibited lower NO production, which was fully corrected by BH 4 and only partially by insulin. ROS generation was increased in diabetic rats, and both BH 4 and insulin normalized it. Diabetes did not change SOD activity and gene expression. However, insulin increased SOD activity but not its expression. Our data suggest that, similarly to males, endothelial dysfunction in female diabetic rats involves an altered ROS/NO imbalance. In contrast to males, however, insulin does not regulate NOS in the microcirculation of diabetic females.

Alzheimer's disease is a neurodegenerative disorder with no cure and not completely understood mechanisms. This devastating disease is one of the main causes of dementia in elderly people worldwide. Among different mechanisms of neuronal death associated to Alzheimer's disease, oxidative stress can be considered as one of the most studied. Several data from literature in this field have shown that oxidative stress seems to be a critical step in the neurodegenerative course of the disease. Clinical trials using antioxidants have described conflicting results, some of them supporting the importance of the use of antioxidant compounds to ameliorate disease's symptoms and the others showing negative results in terms of beneficial effects of antioxidant therapy in the disease progression.

The Na + /K + -ATPase is an integral membrane ion pump, essential to maintaining osmotic balance in cells in the presence of cardiotonic steroids; more specifically, ouabain can be an endogenous modulator of the Na + /K + -ATPase. Here, we conducted a systematic review of the in vitro effects of cardiotonic steroids on Ca 2+ in the brain of rats and mice. Methods: The review was carried out using the PubMed, Virtual Health Library, and EMBASE databases (between 12 June 2020 and 30 June 2020) and followed the guidelines described in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Results: in total, 829 references were identified in the electronic databases; however, only 20 articles were considered, on the basis of the inclusion criteria. The studies demonstrated the effects of ouabain on Ca 2+ signaling in synaptosomes, brain slices, and cultures of rat and mouse cells. In addition to the well-known cytotoxic effects of high doses of ouabain, resulting from indirect stimulation of the reverse mode of the Na + /Ca 2+ exchanger and increased intracellular Ca 2+ , other effects have been reported. Ouabain-mediated Ca 2+ signaling was able to act increasing cholinergic, noradrenergic and glutamatergic neurotransmission. Furthermore, ouabain significantly increased intracellular signaling molecules such as InsPs, IP3 and cAMP. Moreover treatment with low doses of ouabain stimulated myelin basic protein synthesis. Ouabain-induced intracellular Ca 2+ increase may promote the activation of important cell signaling pathways involved in cellular homeostasis and function. Thus, the study of the application of ouabain in low doses being promising for application in neurological diseases. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020204498 , identifier CRD42020204498.

Studies on the abuse potential of modafinil, a psychostimulant-like drug used to treat narcolepsy, are still controversial. While some studies claim no potential for abuse, increasing evidence suggests that modafinil induces abuse-related effects, including rapid-onset behavioral sensitization (i.e., a type of sensitization that develops within hours from the drug priming administration). The rapid-onset sensitization paradigm is a valuable tool to study the neuroplastic changes that occur quickly after drug administration, and shares neuroadaptations with drug abuse in humans. However, the mechanisms involved in the rapid-onset behavioral sensitization induced by modafinil are uncertain. Our aim was to investigate the possible involvement of dopamine D1 and D2 receptors on acute modafinil-induced hyperlocomotion and on the induction and expression of rapid-onset behavioral sensitization induced by modafinil in male Swiss mice. Treatment with the D1 receptor antagonist SCH 23390 or the D2 receptor antagonist sulpiride attenuated the acute modafinil-induced hyperlocomotion in a dose-dependent manner. Pretreatment with either antagonist before the priming injection of modafinil prevented the development of sensitization in response to a modafinil challenge 4 h later. However, only SCH 23390 decreased the expression of modafinil-induced rapid-onset behavioral sensitization. Taken together, the present findings provide evidence of the participation of D1 and D2 receptors on the development of rapid-onset behavioral sensitization to modafinil, and point to a prominent role of D1 receptors on the expression of this phenomenon.

There is substantial controversy about the addictive potential of modafinil, a wake-promoting drug used to treat narcolepsy, proposed as pharmacotherapy for cocaine abuse, and used indiscriminately by healthy individuals due to its positive effects on arousal and cognition. The rapid-onset type of behavioral sensitization (i.e., a type of sensitization that develops within a few hours from the drug priming administration) has been emerged as a valuable tool to study binge-like patterns of drug abuse and the neuroplastic changes that occur quickly after drug administration that ultimately lead to drug abuse. Our aim was to investigate the possible development of rapid-onset behavioral sensitization to modafinil and bidirectional rapid-onset cross-sensitization with cocaine in male Swiss mice. A priming injection of a high dose of modafinil (64 mg/kg) induced rapid-onset behavioral sensitization to challenge injections of modafinil at the doses of 16, 32, and 64 mg/kg, administered 4 h later. Furthermore, rapid-onset cross-sensitization was developed between modafinil and cocaine (64 mg/kg modafinil and 20 mg/kg cocaine), in a bidirectional way. These results were not due to residual levels of modafinil as the behavioral effects of the priming injection of modafinil were no longer present and modafinil plasma concentration was reduced at 4 h post-administration. Taken together, the present findings provide preclinical evidence that modafinil can be reinforcing and can enhance the reinforcing effects of stimulants like cocaine within hours after administration.