The Requirement of L-Type Voltage-Dependent Calcium Channel (L-VDCC) in the Rapid-Acting Antidepressant-Like Effects of Scopolamine in Mice.

Background: Previous studies have shown that a low dose of scopolamine produces rapid-acting antidepressant-like actions in rodents. Understanding the mechanisms underlying this effect and the dose-dependent variations of drug responses remains an important task. L-type voltage-dependent calcium channels were found to mediate rapid-acting antidepressant effects of certain medications (e.g., ketamine). Therefore, it is of great interest to determine the involvement of L-type voltage-dependent calcium channels in the action of scopolamine. Methods: Herein, we investigated the mechanisms underlying behavioral responses to various doses of scopolamine in mice to clarify the involvement of L-type voltage-dependent calcium channels in its modes of action. Open field test, novel object recognition test, and forced swimming test were performed on mice administered varied doses of scopolamine (0.025, 0.05, 0.1, 1, and 3 mg/kg, i.p.) alone or combined with L-type voltage-dependent calcium channel blocker verapamil (5 mg/kg, i.p.). Then, the changes in brain-derived neurotrophic factor and neuropeptide VGF (nonacronymic) levels in the hippocampus and prefrontal cortex of these mice were analyzed. Results: Low doses of scopolamine (0.025 and 0.05 mg/kg) produced significant antidepressant-like effects in the forced swimming test, while higher doses (1 and 3 mg/kg) resulted in significant memory deficits and depressive-like behaviors. Moreover, the behavioral changes in responses to various doses may be related to the upregulation (0.025 and 0.05 mg/kg) and downregulation (1 and 3 mg/kg) of brain-derived neurotrophic factor and VGF in the hippocampus and prefrontal cortex in mice. We further found that the rapid-acting antidepressant-like effects and the upregulation on brain-derived neurotrophic factor and VGF produced by a low dose of scopolamine (0.025 mg/kg) were completely blocked by verapamil. Conclusions: These results indicate that L-type voltage-dependent calcium channels are likely involved in the behavioral changes in response to various doses of scopolamine through the regulation of brain-derived neurotrophic factor and VGF levels.

Curcumin attenuates surgery-induced cognitive dysfunction in aged mice.

Post-operative cognitive dysfunction (POCD) is associated with elderly patients undergoing surgery. However, pharmacological treatments for POCD are limited. In this study, we found that curcumin, an active compound derived from Curcuma longa, ameliorated the cognitive dysfunction following abdominal surgery in aged mice. Further, curcumin prevented surgery-induced anti-oxidant enzyme activity. Curcumin also increased brain-derived neurotrophic factor (BDNF)-positive area and expression of pAkt in the brain, suggesting that curcumin activated BDNF signaling in aged mice. Furthermore, curcumin neutralized cholinergic dysfunction involving choline acetyltransferase expression induced by surgery. These results strongly suggested that curcumin prevented cognitive impairments via multiple targets, possibly by increasing the activity of anti-oxidant enzymes, activation of BDNF signaling, and neutralization of cholinergic dysfunction, concurrently. Based on these novel findings, curcumin might be a potential agent in POCD prophylaxis and treatment.

Extracellular vesicles: A new communication paradigm of complement in neurological diseases.

The complement system is crucial to the innate immune system. It has the function of destroying pathogens by activating the classical, alternative, and lectin pathways. The complement system is important in nervous system diseases such as cerebrovascular and neurodegenerative diseases. Activation of the complement system involves a series of intercellular signaling and cascade reactions. However, research on the source and transport mechanisms of the complement system in neurological diseases is still in its infancy. Studies have increasingly found that extracellular vesicles (EVs), a classic intercellular communication paradigm, may play a role in complement signaling disorders. Here, we systematically review the EV-mediated activation of complement pathways in different neurological diseases. We also discuss the prospect of EVs as future immunotherapy targets.

Distribution of microplastic contamination in the major tributaries of the Yellow River on the Loess Plateau.

Microplastic pollution in rivers had gained increased attention worldwide. However, the differences in microplastic characteristics among major tributaries of large rivers and the environmental factors influencing these characteristics remain uncertain. Through field investigation and indoor experiments, the distribution of microplastics and their driving factors were investigated at 96 sampling sites along the three main tributaries (Huangfuchuan, Wuding and Yan River) of the Yellow River in the Loess Plateau. The results revealed that the average microplastic abundance followed this order: Yan River (430.30 items kg-1) > Wuding River (145.09 items kg-1) > Huangfuchuan River (253.33 items kg-1). The abundance was lower than that in most parts of the world. There was a generally increasing trend in average microplastic abundance from upstream to downstream in the three rivers. The most frequently observed microplastic colors observed were black and white, and the most common polymer type were PE and PS in all three rivers. The dominant shape and size in the three rivers were fiber and particles measuring 0.5-5.0 mm, all accounting for more than half of the total microplastic content. The microplastic abundance, shape, and size were primarily influenced by mean annual precipitation and population density. This relationship can be attributed to the fact that increased population density driven by higher demand and consumption of plastic products, while augmented rainfall aggravated the occurrence of floods and provided conditions for plastic degradation and accumulation. This study will provide fundamental data for pollution assessing and ecological protection of the Yellow River, and provide a certain reference for future management and protection on the Loess Plateau.

Nanomedicine: An Emerging Novel Therapeutic Strategy for Hemorrhagic Stroke.

Hemorrhagic stroke is one of the most devastating diseases worldwide due to a high rate of disability and mortality with few effective treatments. Recent advances in nanomedicines to promote hemostasis, drug delivery, neuroprotection, and nerve regeneration may provide insight into hemorrhagic stroke treatment. In this review, we first view the pathophysiology and conventional therapeutics of hemorrhagic stroke. Second, we comprehensively summarize the current nanomedicines applied in hemorrhagic stroke, including inorganic nanomaterials, polymer-based nanomaterials, lipid-based nanomaterials, self-assembling peptide-based hydrogel, exosomes, and gel systems. Finally, the challenges, opportunities, and future perspectives of nanomedicines for hemorrhagic stroke are discussed. Thus, this review promotes greater exploration of effective therapies for hemorrhagic stroke with nanomedicines.

Genetics of Spontaneous Intracerebral Hemorrhage: Risk and Outcome.

Spontaneous intracerebral hemorrhage (ICH) is a common fatal event without an effective therapy. Of note, some familial aggregation and inherited tendency is found in ICH and heritability estimates indicate that genetic variations contribute substantially to ICH risk and outcome. Thus, identification of genetic variants that affect the occurrence and outcome may be helpful for ICH prevention and therapy. There are several reviews summarizing numerous genetic variants associated with the occurrence of ICH before, but genetic variants contributing to location distribution and outcome have rarely been introduced. Here, we summarize the current knowledge of genetic variants and pay special attention to location distribution and outcome. So far, investigations have reveled variations in APOE, GPX1, CR1, ITGAV, PRKCH, and 12q21.1 are associated with lobar ICH (LICH), while ACE, COL4A2, 1q22, TIMP1, TIMP2, MMP2, MMP9, and TNF are associated with deep ICH (DICH). Moreover, variations in APOE, VWF, 17p12, HP, CFH, IL6ST, and COL4A1 are possible genetic contributors to ICH outcome. Furthermore, the prospects for ICH related genetic studies from the bench to the bed were discussed.

Dimeric Tacrine(10)-hupyridone as a Multitarget-Directed Ligand To Treat Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder with multiple pathological features. Therefore, a multitarget-directed ligands (MTDLs) strategy has been developed to treat AD. We have previously designed and synthesized dimeric tacrine(10)-hupyridone (A10E), a novel tacrine derivative with acetylcholinesterase (AChE) inhibition and brain-derived neurotrophic factor (BDNF) activation activity, by linking tacrine and a fragment of huperzine A. However, it was largely unknown whether A10E could act on other AD targets and produce cognitive-enhancing ability in AD animal models. In this study, A10E could prevent cognitive impairments in APP/PS1 transgenic mice and ß-amyloid (Aß) oligomers-treated mice, with higher potency than tacrine and huperzine A. Moreover, A10E could effectively inhibit Aß production and deposition, alleviate neuroinflammation, enhance BDNF expression, and elevate cholinergic neurotransmission in vivo. At nanomolar concentrations, A10E could inhibit Aß oligomers-induced neurotoxicity via the activation of tyrosine kinase receptor B (TrkB)/Akt pathway in SH-SY5Y cells. Furthermore, Aß oligomerization and fibrillization could be directly disrupted by A10E. Importantly, A10E at high concentrations did not produce obvious hepatotoxicity. Our results indicated that A10E could produce anti-AD neuroprotective effects via the inhibition of Aß aggregation, the activation of the BDNF/TrkB pathway, the alleviation of neuroinflammation, and the decrease of AChE activity. As MTDLs could produce additional benefits, such as overcoming the deficits of drug combination and enhancing the compliance of AD patients, our results also suggested that A10E might be developed as a promising MTDL lead for the treatment of AD.

Tacrine(10)-Hupyridone Prevents Post-operative Cognitive Dysfunction via the Activation of BDNF Pathway and the Inhibition of AChE in Aged Mice.

Post-operative cognitive dysfunction (POCD) could cause short-term or long-term cognitive disruption lasting weeks or months after anesthesia and surgery in elderly. However, no effective treatment of POCD is currently available. Previous studies indicated that the enhancement of brain-derived neurotrophic factor (BDNF) expression, and the elevation the cholinergic system, might be effective to prevent POCD. In this study, we have discovered that tacrine(10)-hupyridone (A10E), a novel acetylcholinesterase (AChE) inhibitor derived from tacrine and huperzine A, could prevent surgery-induced short-term and long-term impairments of recognition and spatial cognition, as evidenced by the novel object recognition test and Morris water maze (MWM) tests, in aged mice. Moreover, A10E significantly increased the expression of BDNF and activated the downstream Akt and extracellular regulated kinase (ERK) signaling in the surgery-treated mice. Furthermore, A10E substantially enhanced choline acetyltransferase (ChAT)-positive area and decreased AChE activity, in the hippocampus regions of surgery-treated mice, indicating that A10E could prevent surgery-induced dysfunction of cholinergic system, possibly via increasing the synthesis of acetylcholine and the inhibition of AChE. In conclusion, our results suggested that A10E might prevent POCD via the activation of BDNF pathway and the inhibition of AChE, concurrently, in aged mice. These findings also provided a support that A10E might be developed as a potential drug lead for POCD.