Neuroprotective efficacy of the bacterial metabolite, prodigiosin, against aluminium chloride-induced neurochemical alternations associated with Alzheimer's disease murine model: Involvement of Nrf2/HO-1/NF-κB signaling.

Prodigiosin (PDG) is a bacterial metabolite with numerous biological and pharmaceutical properties. Exposure to aluminium is considered a root etiological factor in the pathological progress of Alzheimer's disease (AD). Here, in this investigation, we explored the neuroprotective potential of PDG against aluminium chloride (AlCl3 )-mediated AD-like neurological alterations in rats. For this purpose, rats were gavaged either AlCl3 (100 mg/kg), PDG (300 mg/kg), or both for 42 days. As a result of the analyzes performed on the hippocampal tissue, it was observed that AlCl3 induced biochemical, molecular, and histopathological changes like those related to AD. PDG pre-treatment significantly decreased acetylcholinesterase activity and restored the levels of brain-derived neurotrophic factor, monoamines (dopamine, norepinephrine, and serotonin), and transmembrane protein (Na+ /K+ -ATPase). Furthermore, PDG boosted the hippocampal antioxidant capacity, as shown by the increased superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione contents. These findings were accompanied by decreases in malondialdehyde and nitric oxide levels. The antioxidant effect may promote the upregulation of the expression of antioxidant genes (Nrf2 and HO-1). Moreover, PDG exerted notable anti-inflammatory effects via the lessening of interleukin-1 beta, tumor necrosis factor-alpha, cyclooxygenase-2, nuclear factor kappa B, and decreases in the gene expression of inducible nitric oxide synthase. In addition, noteworthy decreases in pro-apoptotic (Bax and caspase-3) levels and increases in anti-apoptotic (Bcl-2) biomarkers suggested an anti-apoptotic effect of PDG. In support, the hippocampal histological examination validated the aforementioned changes. To summarize, the promising neuromodulatory, antioxidative, anti-inflammatory, and anti-apoptotic activities of PDG establish it as a potent therapeutic option for AD.

Therapeutic antischizophrenic activity of prodigiosin and selenium co-supplementation against amphetamine hydrochloride-induced behavioural changes and oxidative, inflammatory, and apoptotic challenges in rats.

Schizophrenia (SCZ), a multifactorial neuropsychiatric disorder, is treated with inefficient antipsychotics and linked to poor treatment outcomes. This study, therefore, investigated the combined administration of prodigiosin (PDG) and selenium (Na2SeO3) against SCZ induced by amphetamine (AMPH) in rats. Animals were allocated into four groups corresponding to their respective 7-day treatments: control, AMPH (2 mg/kg), PDG (300 mg/kg) + Na2SeO3 (2 mg/kg), and AMPH + PDG + Na2SeO3. The model group exhibited biochemical, molecular, and histopathological changes similar to those of the SCZ group. Contrastingly, co-administration of PDG and Na2SeO3 significantly increased the time for social interaction and decreased AChE and dopamine. It also downregulated the gene expression of NMDAR1 and restored neurotrophin (BDNF and NGF) levels. Further, PDG combined with Na2SeO3 improved the antioxidant defence of the hippocampus by boosting the activities of SOD, CAT, GPx, and GR. These findings were accompanied by an increased GSH, alongside decreased MDA and NO levels. Furthermore, schizophrenic rats having received PDG and Na2SeO3 displayed markedly lower IL-1ß and TNF-α levels compared to the model group. Interestingly, remarkable declines in the Bax (pro-apoptotic) and increases in Bcl-2 (anti-apoptotic) levels were observed in the SCZ group that received PDG and Na2SeO3. The hippocampal histological examination confirmed these changes. Collectively, these findings show that the co-administration of PDG and Na2SeO3 may have a promising therapeutic effect for SCZ. This is mediated by mechanisms related to the modulation of cholinergic, dopaminergic, and glutaric neurotransmission and neurotrophic factors, alongside the suppression of oxidative damage, neuroinflammation, and apoptosis machinery.

Selenium Nanoparticles with Prodigiosin Rescue Hippocampal Damage Associated with Epileptic Seizures Induced by Pentylenetetrazole in Rats.

BACKGROUND: Prodigiosin (PDG) is a red pigment synthesized by bacterial species with important pharmaceutical and biological activities. Here, we investigated the neuroprotective and anticonvulsant activities of green biosynthesized selenium formulations with PDG (SeNPs-PDG) versus pentylenetetrazole (PTZ)-induced epileptic seizures. METHODS: Rats were assigned into six experimental groups: control; PTZ (60 mg/kg, epileptic model); sodium valproate (200 mg/kg) + PTZ; PDG (300 mg/kg) + PTZ; sodium selenite (0.5 mg/kg) + PTZ; and SeNPs-PDG (0.5 mg/kg) + PTZ. The treatment duration is extended to 28 days. RESULTS: SeNPs-PDG pre-treatment delayed seizures onset and reduced duration upon PTZ injection. Additionally, SeNPs-PDG enhanced the antioxidant capacity of hippocampal tissue by activating the expression of nuclear factor erythroid 2-related factor 2 and innate antioxidants (glutathione and glutathione derivatives, in addition to superoxide dismutase and catalase) and decreasing the levels of pro-oxidants (lipoperoxidation products and nitric oxide). SeNPs-PDG administration inhibited inflammatory reactions associated with epileptic seizure development by suppressing the production and activity of glial fibrillary acidic protein and pro-inflammatory mediators, including interleukin-1 beta, tumor necrosis factor-alpha, cyclooxygenase-2, inducible nitric oxide synthase, and nuclear factor kappa B. Moreover, SeNPs-PDG protected against hippocampal cell loss following PTZ injection by decreasing the levels of cytosolic cytochrome c, Bax, and caspase-3 and enhancing the expression of anti-apoptotic Bcl-2. Interestingly, SeNPs-PDG restored the PTZ-induced imbalance between excitatory and inhibitory amino acids and improved monoaminergic and cholinergic transmission. CONCLUSIONS: These promising antioxidative, anti-inflammatory, anti-apoptotic, and neuromodulatory activities indicate that SeNPs-PDG might serve as a naturally derived anticonvulsant agent.

A Descriptive-Multivariate Analysis of Community Knowledge, Confidence, and Trust in COVID-19 Clinical Trials among Healthcare Workers in Uganda.

Background-misinformation and mistrust often undermines community vaccine uptake, yet information in rural communities, especially of developing countries, is scarce. This study aimed to identify major challenges associated with coronavirus disease 2019 (COVID-19) vaccine clinical trials among healthcare workers and staff in Uganda. Methods-a rapid exploratory survey was conducted over 5 weeks among 260 respondents (66% male) from healthcare centers across the country using an online questionnaire. Twenty-seven questions assessed knowledge, confidence, and trust scores on COVID-19 vaccine clinical trials from participants in 46 districts in Uganda. Results-we found low levels of knowledge (i.e., confusing COVID-19 with Ebola) with males being more informed than females (OR = 1.5, 95% CI: 0.7-3.0), and mistrust associated with policy decisions to promote herbal treatments in Uganda and the rushed international clinical trials, highlighting challenges for the upcoming Oxford-AstraZeneca vaccinations. Knowledge, confidence and trust scores were higher among the least educated (certificate vs. bachelor degree holders). We also found a high level of skepticism and possible community resistance to DNA recombinant vaccines, such as the Oxford-AstraZeneca vaccine. Preference for herbal treatments (38/260; 14.6%, 95% CI: 10.7-19.3) currently being promoted by the Ugandan government raises major policy concerns. High fear and mistrust for COVID-19 vaccine clinical trials was more common among wealthier participants and more affluent regions of the country. Conclusion-our study found that knowledge, confidence, and trust in COVID-19 vaccines was low among healthcare workers in Uganda, especially those with higher wealth and educational status. There is a need to increase transparency and inclusive participation to address these issues before new trials of COVID-19 vaccines are initiated.

Neuroprotective Efficiency of Prodigiosins Conjugated with Selenium Nanoparticles in Rats Exposed to Chronic Unpredictable Mild Stress is Mediated Through Antioxidative, Anti-Inflammatory, Anti-Apoptotic, and Neuromodulatory Activities.

PURPOSE: Depression is a mood disorder accompanied by intensive molecular and neurochemical alterations. Currently, available antidepressant therapies are not fully effective and are often accompanied by several adverse impacts. Accordingly, the ultimate goal of this investigation was to clarify the possible antidepressant effects of prodigiosins (PDGs) loaded with selenium nanoparticles (PDGs-SeNPs) in chronic unpredictable mild stress (CUMS)-induced depression-like behavior in rats. METHODS: Sixty Sprague Dawley rats were randomly allocated into six groups: control, CUMS group (depression model), fluoxetine (Flu, 10 mg/kg)+CUMS, PDGs+CUMS (300 mg/kg), sodium selenite (Na2SeO3, 400 mg/kg)+CUMS, and PDGs-SeNPs+CUMS (200 mg/kg). All treatments were applied orally for 28 consecutive days. RESULTS: PDGs-SeNPs administration prevented oxidative insults in hippocampal tissue, as demonstrated by decreased oxidant levels (nitric oxide and malondialdehyde) and elevated innate antioxidants (glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase), in addition to the upregulated expression of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 in rats exposed to CUMS. Additionally, PDGs-SeNPs administration suppressed neuroinflammation in hippocampal tissue, as determined by the decreased production of pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1ß, and interleukin-6), increased anti-inflammatory cytokine interleukin-10, and decreased inflammatory mediators (prostaglandin E2, cyclooxygenase-2, and nuclear factor kappa B). Moreover, PDGs-SeNPs administration in stressed rats inhibited neuronal loss and the development of hippocampal apoptosis through enhanced levels of B cell lymphoma 2 and decreased levels of caspase 3 and Bcl-2-associated X protein. Interestingly, PDGs-SeNPs administration improved hormonal levels typically disrupted by CUMS exposure and significantly modulated hippocampal levels of monoamines, brain-derived neurotrophic factor, monoamine oxidase, and acetylcholinesterase activities, in addition to upregulating the immunoreactivity of glial fibrillary acidic protein in CUMS model rats. CONCLUSION: PDGs-SeNPs may serve as a prospective antidepressant candidate due to their potent antioxidant, anti-inflammatory, and neuroprotective potential.

Possible Role of Kaempferol in Reversing Oxidative Damage, Inflammation, and Apoptosis-Mediated Cortical Injury Following Cadmium Exposure.

Cadmium (Cd) is a heavy metal of considerable toxicity, inducing a number of hazardous effects to humans and animals including neurotoxicity. This experiment was aimed to investigate the potential effect of kaempferol (KPF) against Cd-induced cortical injury. Thirty-two adult Sprague-Dawley rats were divided equally into four groups. The control rats intraperitoneally (i.p.) injected with physiological saline (0.9% NaCl), the cadmium chloride (CdCl2)-treated rats were i.p. injected with 4.5 mg/kg of CdCl2, the KPF-treated rats were orally gavaged with 50 mg/kg of KPF, and the KPF + CdCl2-treated rats were administered orally 50 mg/kg of KPF 120 min before receiving i.p. injection of 4.5 mg/kg CdCl2. CdCl2 exposure for 30 days led to the accumulation of Cd in the cortical tissue, accompanied by a reduction in the content of monoamines and acetylcholinesterase activity. Additionally, CdCl2 induced a state of oxidative stress as evidenced by the elevation of lipid peroxidation and nitrate/nitrite levels, while glutathione content and the activities of glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase were decreased. Moreover, CdCl2 mediated inflammatory events in the cortical tissue through increasing tumor necrosis factor-alpha and interleukin-1 beta levels and upregulating the expression of inducible nitric oxide synthase. Furthermore, pro-apoptotic proteins (Bax and caspase-3) were elevated, while Bcl-2, the anti-apoptotic protein, was decreased. Also, histological alterations were observed obviously following CdCl2. However, KPF pretreatment restored significantly the examined markers to be near the normal values. Hence, the obtained data provide evidences that KPF pretreatment has the protective effect to preserve the cortical tissues in CdCl2-exposed rats by restraining oxidative stress, inflammatory response, apoptosis, neurochemical modulation, and improving the histological changes.

Soursop fruit extract mitigates scopolamine-induced amnesia and oxidative stress via activating cholinergic and Nrf2/HO-1 pathways.

Current therapeutic interventions for memory loss are inadequate and are associated with numerous adverse effects. There is an urgent need for new alternative agents for the treatment of memory loss and related disorders. Here, we investigated the potential neuroprotective role of soursop fruit extract (SSFE) in scopolamine (SCO)-induced amnesia and oxidative damage in the hippocampus of rats. Thirty-five rats were randomly allocated into 5 groups: control, SCO, SSFE, SCO, SSFE+SCO and N-acetylcysteine (NAC) + SCO. SCO-treatment increased acetylcholine esterase activity and decreased hippocampal levels of acetylcholine, serotonin, dopamine, norepinephrine, and histamine. The level of ATP increased. SCO-treated rats showed a disturbance in oxidative status, which was evident through the increase in malondialdehyde, and nitrites/nitrates and a decrease in cellular antioxidant molecules including glutathione, superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase. A disturbance was also observed via downregulation of the nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 defense pathways. SCO-treatment enhances a neuroinflammatory state, as indicated by the release of tumor necrosis factor- α and interleukin-1ß and increased inducible nitric oxide synthase and mRNA expression. SCO-treatment decreased the expression of the anti-apoptotic protein, B cell lymphoma 2 and increased the expression of the pro-apoptotic protein, Bcl-2 associated X protein, caspase-3 and cytochrome c in hippocampal neurons. SSFE pretreatment markedly ameliorated hippocampal changes. Our findings revealed that SSFE exerts its potential anti-amnestic effect mainly through the activation of the cholinergic system and Nrf2/HO-1 pathway.

Neuroprotective efficiency of Mangifera indica leaves extract on cadmium-induced cortical damage in rats.

Due to the high ability of cadmium to cross the blood-brain barrier, cadmium (Cd) causes severe neurological damages. Hence, the purpose of this study was to investigate the possible protective effect of Mangifera indica leaf extract (MLE) against Cd-induced neurotoxicity. Rats were divided into eight groups. Group 1 served as vehicle control group, groups 2, 3 and 4 received MLE (100, 200, 300 mg /kg b.wt, respectively). Group 5 was treated with CdCl2 (5 mg/kg b.wt). Groups 6, 7 and 8 were co-treated with MLE and CdCl2 using the same doses. All treatments were orally administered for 28 days. Cortical oxidative stress biomarkers [Malondialdehyde (MDA), nitric oxide (NO), glutathione content (GSH), oxidized form of glutathione (GSSG), 8-hydroxy-2-deoxyguanosine (8-OHdG), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)], inflammatory cytokines [tumor necrosis factor (TNF-α) and interlukin-1ß (IL-1ß)], biogenic amines [norepinephrine (NE), dopamine (DA) and serotonin (5-HT)], some biogenic metabolites [3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA)], acetylcholine esterase activity (AChE) and purinergic compound [adenosine triphosphate (ATP)] were determined in frontal cortex of rats. Results indicated that Cd increased levels of the oxidative biomarkers (MDA, NO, GSSG and 8-OHdG) and the inflammatory mediators (TNF-α and IL-1ß), while lowered GSH, SOD, CAT, GPx and ATP levels. Also, Cd significantly decreased the AChE activity and the tested biogenic amines while elevated the tested metabolites in the frontal cortex. Levels of all disrupted cortical parameters were alleviated by MLE co-administration. The MLE induced apparent protective effect on Cd-induced neurotoxicity in concern with its medium and higher doses which may be due to its antioxidant and anti-inflammatory activities.