Current Neuropharmacology - Current Issue

This study aims to guide the diagnosis and treatment of hepatolenticular degeneration (also named Wilson's disease, WD) and aid multidisciplinary clinicians in making reasonable and personalized treatment regimens.

The authors aim to establish a systemic structure for Chinese Multidisciplinary Expert Consensus on Diagnosis and Treatment of Hepatolenticular Degeneration.

We collaborated with experts from relevant branches of the Chinese Medical Association and multiple disciplines, along with statistical experts, to formulate this consensus. It is based on advancements in basic and clinical research on Wilson's disease, both domestically and internationally.

It mainly consists of clinical manifestations, diagnosis, differential diagnosis, management, and prognosis in the context of Multi-Department treatment (MDT) in China.

This Chinese consensus incorporates four decades of institutional experience with thousands of Chinese Wilson’s disease (WD) inpatients, as well as decades of international inpatient cases from East to West. It is hoped that this consensus will garner broader attention from clinicians worldwide.

E-cigarettes (EC) have been shown to impair memory by disrupting the balance involving ROS and antioxidant enzymes, leading to oxidative stress. Vitamin C (VitC) is a strong antioxidant with cell protective efficacy and scavenges free radicals. The present study evaluated VitC for potential protective effects against EC-induced memory impairment in rat models.

The animals were exposed to EC for 2 hr/day, with a one-hour break in between, for five days per week over four weeks. Simultaneously, animals were administered Vitamin C at 100 mg/ kilogram/bw/day via oral gavage five days/week/for four weeks. After the treatment and exposure period concluded, spatial learning and memory were evaluated using the Radial Arms Water Maze. Furthermore, the oxidative stress biomarkers levels (GSSG, GSH, GSH/GSSG, TBARS, Catalase, and GPx) and brain-derived neurotrophic factor (BDNF) were measured in the hippocampus tissues.

The findings indicated that EC had a detrimental effect on the short-term and long-term memory of the animals (p < 0.05). Additionally, EC decreased the levels of GPx, SOD, GSH, the GSH/GSSG ratio, and BDNF (p < 0.05). Furthermore, the GSSG level was significantly elevated (p < 0.05) by EC. However, Vitamin C prevented impairment of memory and restored levels of biomarkers of oxidative stress and BDNF.

To summarize, exposure to EC resulted in impairments of memory, both short-term and long-term. However, the administration of Vitamin C prevented these negative effects by its antioxidant properties.

Siegesbeckia orientalis L. (SO) is a traditional Chinese herbal medicine commonly used for inflammatory diseases. In ancient, SO is applied for stroke, but mechanisms have not been clear. The purpose is to investigate whether SO exerts neuroprotective effects by reducing microglia-related inflammatory injury after focal cerebral ischemia/reperfusion (I/R).

SO was extracted using 50% ethanol and quality control was performed by Waters ACQUITY-UPLC CLASS system. The focal cerebral I/R model was established in mice, neurological functions, weight loss and infarct volume was evaluated. Microglial status in penumbra was monitored by immunofluorescence staining and morphology. Mouse primary microglia was subjected to lipopolysaccharide stimulation for triggering inflammatory response, meanwhile microglia-neuron co-culture model was established in vitro. Apoptosis and pyroptosis for neurons were demonstrated using TUNEL assay, western blot and ELISA. Inflammatory cytokines were detected by qPCR and ELISA.

SO treatment reduced infarct volume, improved neurological functions, lessened neuronal apoptosis and pyroptosis shown by increased Bcl-2/Bax ratio, decreased cleaved Caspase-3 and suppressed NLRP3/Caspase-1/GSDMD expression after I/R. Moreover, microglial status from pro-inflammation to anti-inflammation was characterized by morphological change and increasing percentage of CD206/Iba1 positive cells after SO treatment. Additionally, SO decreased TLR4 and nuclear-located p65 expression, suppressed IL-1β, IL-6, IL-18, and TNF-α, but increased IL-10 secretion both in vivo and vitro.

SO reverses pro-inflammatory status of microglia as evidenced by suppression of TLR4/NF-κB cascade, down-regulation of pro-inflammatory cytokines and up-regulation of anti-inflammatory cytokines, which contributes to its neuroprotective against neuronal pyroptosis and apoptosis after ischemic stroke.

Quercetin, a naturally occurring flavonoid, has been reported to possess several pharmacological activities including neuroprotective properties. Chronic alcohol exposure is known to cause apoptotic neurodegeneration. In this study, docking studies were used to investigate the ligand-protein affinity against various neuroinflammatory targets like ChAt, TNF, IL-6, and IL-1β. Next, molecular studies were performed to determine quercetin activity against chronic ethanol-induced neurodegeneration in the adult rat cortex.

Adult rats were treated with ethanol for 3 months while quercetin was treated for the last 20 days along with ethanol to the respective experimental groups. Elements of the mitochondrial apoptotic pathway i.e. pro-apoptotic protein Bax, cytochrome C release, and activation of caspase-9 and caspase-3 were determined after respective drug treatment. Our docking results revealed that quercetin possesses neuroprotective potential by targeting neuroinflammatory proteins inhibiting neurodegeneration.

Western blot results showed that ethanol administration increased the protein expressions of Bax, cytochrome C, caspase-9, and caspase-3. Furthermore, DNA damage was also observed by chronic ethanol treatment with increased expression of PARP-1. Quercetin treatment offered neuroprotection in the cortex against ethanol-induced neurodegeneration. Quercetin reversed the ethanol-induced apoptotic trend via down-regulating Bax, preventing cytochrome C release and inhibition of caspase cascade.

Immunohistological findings i.e. caspase-3 immunoreactivity, Nissl staining, and Fluoro-Jade B staining also revealed significant neuronal survival with quercetin treatment against ethanol-induced neuronal cell death. Our in-silico and in-vivo findings suggest that quercetin has the potential capability to be used as a neuroprotective agent against alcoholic neurotoxicity.

Disease-modifying therapies (DMTs) are aimed at controlling Multiple Sclerosis disease by modulating or suppressing the immune system. However, there is limited data on changes in immune cell subsets induced by these treatments.

To assess differences in myeloid, T-, and B-cell subsets in the peripheral blood of relapsing-remitting MS (RR-MS) patients treated with different DMTs.

This longitudinal study enrolled all RR-MS patients treated with cladribine (CLAD), dimethyl fumarate (DMF), and natalizumab (NTZ) between July 2022 and September 2022. All patients underwent blood sample collection with flow cytometry at baseline (T0; before starting treatment) and 24 ± 3 months after treatment initiation (T1).

Forty-three RR-MS patients (83.7% women; mean age 34.7 ± 11.1 years; median EDSS: 2.0, IQR: 1.0-2.8) were enrolled. Among them, 24 (55.8%) were treated with DMF, 10 (23.3%) with NTZ, and 9 (20.9%) with CLAD. At T1, patients assigned to CLAD showed a reduction in B-cell memory-switched (p = .029), B-cell memory-unswitched (p = .08), and B-cell naïve resting (p = .029). Additionally, the T and NK cell compartments showed a reduction in the percentage of CD3/CD4/CD127/CD45RA/CD161+ (p = .057). In the NTZ group, a significant decrease in the percentage of CD3/CD4/CD127/CD45RA/CD161+ (p = .029) was observed. A reduced percentage of mature naïve B cells (p = .057) and B memory-unswitched (p = .059) was observed in the DMF group. No significant differences were found in the myeloid subsets.

DMTs induced significant modifications in B- and T-cell compartments. Characterizing these immunologic changes could deepen our understanding of the mechanisms of action of different therapies.

Alzheimer's disease (AD) is a neurological disorder characterized by cognitive decline and behavioral distrubance which are expected to significantly affect the patient's quality of life. Previous studies revealed the neuroprotective effects of progesterone. Furthermore, the aim of this study was to assess the neuroprotective potentials of new derivatives of progesterone (AN-1 to AN-5).

Following compound synthesis and structure elucidation, in vitro antioxidant (DPPH), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, as well as molecular docking studies, were performed, according to the standard procedures and the most potent compound was then subjected to more detailed behavioral studies, including the Y-Maze, Elevated Plus Maze (EPM), and open field tests in scopolamine-induced amnesic animals.

In the DPPH assay, the AN-1 compound at 1000 µg/ml concentration exhibited 83.37 ± 2.03% inhibition of DPPH free radicals with an IC50 value of 57.21 µM. Likewise, the compound AN-1 demonstrated 88.94 ± 1.20% inhibition against AChE and 86.78 ± 1.24% inhibition against BChE enzymes at 1000 µg/ml with IC50 values of 56.52 and 43.33 µM, correspondingly. In behavioral studies, compound AN-1 demonstrated a significant decline in cognitive impairments and improved working memory as well as locomotor activities of the amnesic animals. Molecular docking studies also demonstrated that the compound AN-1 has promising inhibitory potentials against AChE and BChE enzymes by binding to their active site amino acid residues. The binding energies of AN-1 with both enzymes were -7.6 Kcal/mol for AChE and -8.1 Kcal/mol for BChE.

Based on our findings, it is concluded that the derivatives of progesterone exhibit neuroprotective potential, and further research is needed to extend their neuroprotective role in the treatment of AD.