Safety Profile of Intravenous Ferulic Acid Nanoparticles: Acute Toxicity and Neurological Effects in Sprague-Dawley Rats

In the past, scientists focused on the development of antidotes (mainly anticholinergics in combination with reactivators of inhibited acetylcholinesterase-oximes) to increase the number of surviving nerve agent-intoxicated individuals. Recently, they are interested in antidotes able not only to protect nerve agent-poisoned men from lethal toxic effects but also to improve their life quality by improvement of their central cognitive functions. In our study, the water maze was used to measure spatial working learning and memory in the case of tabun-induced cognitive impairment in albino Wistar rats. Antidotal treatment consisted of atropine alone or a combination of atropine with an oxime (obidoxime, trimedoxime or oxime HI-6). Our results suggest that atropine alone is not sufficient as a treatment for saving cognitive functions impaired by tabun. On the other hand, the addition of oxime to atropine contributes to improvement of cognitive performance in tabun-poisoned rats regardless of type of oxime.

Schisandrin is one of the main active compounds isolated from the fruit of Schisandrae chinensis Fructus, which is scientifically proven to have beneficial effects on Alzheimer’s disease (AD) treatment at the cellular and whole organism level. However, the oral availability of schisandrin is very low, thus implying that the underlying mechanism of therapeutic effect on AD treatment is yet to be clarified fully. Therefore, we speculated that the therapeutic effect of schisandrin on AD is mainly by regulating the imbalance of the gut microbiota (GM). In this study, behavioral experiments and H&E staining were used to confirm the pharmacological effects of schisandrin on rats with AD. 16S rDNA gene sequencing and feces, plasma, and brain metabolomics techniques were utilized to investigate the therapeutic effects and the underlying mechanisms of schisandrin on cognitive impairment in rats with AD. The results indicated that schisandrin improved cognitive impairment and hippocampal cell loss in rats. The UPLC-QTOF/MS-based metabolomics studies of the feces, plasma, and brain revealed that 44, 96, and 40 potential biomarkers, respectively, were involved in the treatment mechanism of schisandrin. Schisandrin improved the metabolic imbalance in rats with AD, and the metabolic changes mainly affected the primary bile acid biosynthesis, sphingolipid metabolism, glycerophospholipid metabolism, and unsaturated fatty acid biosynthesis. Schisandrin can improve the GM structure disorder and increase the abundance of beneficial bacteria in the gut of rats with AD. The predictive metagenomics analysis indicated that the altered GM was mainly involved in lipid metabolism, steroid hormone biosynthesis, arachidonic acid metabolism, biosynthesis of unsaturated fatty acids, and bacterial invasion of epithelial cells. Spearman’s correlation analysis showed a significant correlation between affected bacteria and metabolites in various metabolic pathways. Overall, the data underline that schisandrin improves the cognitive impairment in rats with AD by affecting the composition of the GM community, thus suggesting the potential therapeutic effect of schisandrin on the brain–gut axis in rats with AD at the metabolic level.

Traumatic brain injury (TBI) is a chronic condition that causes permanent disability, particularly cognitive impairment resulting from glial scar formation. Minocycline treatment inhibits glial scar formation through the Ciliary Neurotropic Factor (CNTF) pathway in multiple sclerosis. We hypothesized that minocycline could also inhibit CNTF, which would play a role in the inhibition of glial scar formation in TBI. The objective was to evaluate the role of minocycline in inhibiting glial scar formation through the CNTF signaling pathway and ameliorating cognitive impairment in TBI model rats. Male Sprague Dawley rats (n = 16) were divided into 4 groups (n = 4/group). TBI through the weight drop model is performed on day 0, followed by minocycline treatment of 25 mg/kg (MNO1 group), 50 mg/kg (MNO2 group) and 100 mg/kg (MNO3 group) given for 14 days. The NOR test is performed on day 15, followed by immunofluorescence double staining on day 16. Minocycline plays a role in inhibiting glial scar formation in TBI model rats. Minocycline inhibits the formation of CNTF with an effect proportion of 66.3 %, which plays a role in inhibiting glial scar in the perilesional area in TBI model rats. Inhibition of glial scar improves cognitive function impairment in TBI model rats. Administration of minocycline improves cognitive function in TBI model rats with an effect proportion of 46.7 %. It can be concluded that minocycline inhibits glial scar through the inhibition of CNTF expression and ameliorates cognitive impairment in a rat model of TBI.

Alzheimer’s disease is a devastating neurodegenerative disorder, the most common among the dementing illnesses. Acetaminophen has gaining importance in neurodegenerative diseases by attenuating the dopaminergic neurodegeneration in Caenorhabditis elegans model, decreasing the chemokines and the cytokines and increasing the anti apoptotic protein such as Bcl-2 in neuronal cell culture. The low concentration acetaminophen improved the facilitation to find the hidden platform in Morris Water Maze Test. Also some data suggest that acetaminophen could contribute in neurodegeneration. The present study was aimed to evaluate the effect of acetaminophen against colchicine induced cognitive impairment and oxidative stress in wistar rats. The cognitive learning and memory behaviour was assessed using step through passive avoidance paradigm and acetylcholine esterase activity. The parameters of oxidative stress were assessed by measuring the malondialdehyde, reduced glutathione and catalase levels in the whole brain homogenates. There was a significant memory improvement in the rats received acetaminophen treatment and it has also decreased the acetylcholine esterase enzyme level, confirming its nootropic activity. Acetaminophen neither increases nor decreases the reduced glutathione and catalase in the whole brain homogenates, showing that acetaminophen is devoid of any adverse effect on brain antioxidant defense system.

A long noncoding RNA LOC103690121 promotes hippocampus neuronal apoptosis in streptozotocin-induced type 1 diabetes

Electroacupuncture Ameliorates Cognitive Impairment and Spontaneous Low-Frequency Brain Activity in Rats with Ischemic Stroke

Introduction: Commiphora caudata contains various essential phytoconstituents and is a potential medicinal plant used traditionally to treat various ailments such as neurodegenerative diseases. The present study aimed to evaluate the neuroprotective effect of ethanolic leaf extract of Commiphora caudata against the lipopolysaccharides (LPS) induced behavioral changes in rats. Methods: The in-vitro antioxidant potential was evaluated by 1-diphenyl-2-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assay methods. For in-vivo studies, the animals were pre-treated with ethanolic leaf extract of Commiphora caudata (EECC) at 200 and 400 mg/kg of b.w for 30 days, and neurotoxicity was induced with a single intraperitoneal injection of LPS 1 mg/kg, b.w on day 31. The neurotoxicity was evaluated with a chain of behavioral tests such as the Morris water maze test, radial arm maze, and choice reaction time (CRT) tests. At the end of the study, rats were sacrificed, the brain hippocampal region was removed, and the levels of acetylcholinesterase, nitric oxide, and protein were measured. Results: The IC50 value in the DPPH method was 71.58 ± 15.62 μg, and the total antioxidant activity of EECC was found to be 742.33 ± 14.57 μmol Fe (II)/g extract. In behavioral tests, animals treated with EECC at 200 and 400 mg/kg showed a neuroprotective effect in the Morris water maze test, an 8-arm radial maze test, and in the CRT test. Both doses reduced acetylcholinesterase, nitric oxide, and protein levels (P < 0.001), respectively. Conclusion: The present study results showed the promising neuroprotective effects of ethanolic extract of leaves of Commiphora caudata and its action against the LPS-induced cognitive impairment in rats.

Inhaled anesthetics are known to induce neurotoxicity in the developing brains of rodents, although the mechanisms are not well understood. The aim of this study was to elucidate the molecular mechanisms underlying anesthetics-induced neurodevelopmental toxicity by VEGF receptor 2 (VEGFR2) through the interaction between microglia and neural stem cells (NSCs) in postnatal day 7 (P7) rats. Cognitive function of P7 rats exposed to isoflurane and sevoflurane were assessed using Morris Water Maze and T maze tests. We also evaluated the expression levels of NSC biomarkers (Nestin and Sox2), microglia biomarker (CD11b or or IBA1), pro-inflammatory cytokines (IL-6 and TNF-α), and VEGFR2 using western blotting and immunohistochemistry in the brains of control and anesthesia-treated rats. We found spatial learning and working memory was impaired 2 weeks after anesthetics exposure in rats. Isoflurane induced stronger and more prolonged neurotoxicity than sevoflurane. However, cognitive functions were recovered 6 weeks after anesthesia. Isoflurane and sevoflurane decreased the levels of Nestin, Sox2, and p-VEGFR2, activated microglia, decreased the number of NSCs and reduced neurogenesis and the proliferation of NSCs, and increased the levels of IL-6, TNF-α, and CD11b. Our results suggested that isoflurane and sevoflurane induced cognitive impairment in rats by inhibiting NSC development and neurogenesis via microglial activation, neuroinflammation, and suppression of VEGFR2 signaling pathway.

Cerebral ischemia aggravates cognitive impairment in a rat model of Alzheimer's disease

Luteolin rescues pentylenetetrazole-induced cognitive impairment in epileptic rats by reducing oxidative stress and activating PKA/CREB/BDNF signaling.

Wheat embryo globulin nutrients ameliorate d-galactose and aluminum chloride-induced cognitive impairment in rats

Clitoria ternatea, commonly known as Aparajita, is used as Medhya rasayana in Ayurveda. The role of C. ternatea in experimental models of cognitive impairment is yet to be explored. The present study was designed to study the effect of aqueous and hydroalcoholic extracts of C. ternatea on biochemical and behavioral parameters related to cognitive impairment in in vitro and in vivo studies. In vitro free radical scavenging and enzyme-inhibitory (cholinesterase, glycogen synthase kinase-3-β, rho kinase, prolyl endopeptidase, catechol-O-methyl transferase, and lipoxygenase) activities of aqueous and hydroalcoholic extracts of C. ternatea plant were evaluated. Based on in vitro results, hydroalcoholic extract of C. ternatea (100, 300, and 500mg/kg, p.o.) was selected for evaluation in intracerebroventricularly injected streptozotocin (STZ)-induced cognitive impairment in male Wistar rats. Behavioral assessment was performed at baseline and on the 14th, 21st, and 28th days after STZ injection using elevated plus maze, passive avoidance, Morris water maze, and photoactometer. Oxidative stress parameters (malondialdehyde, reduced glutathione, nitric oxide levels, and superoxide dismutase activity), cholinesterase activity, and rho kinase (ROCK II) expression were studied in cerebral cortex and hippocampus of rats' brain at the end of the study. The hydroalcoholic extract possessed significantly more in vitro antioxidant and enzyme-inhibitory activities as compared to aqueous extract. The hydroalcoholic extract of C. ternatea prevented STZ-induced cognitive impairment dose dependently by reducing oxidative stress, cholinesterase activity, and ROCK II expression. In vitro and in vivo results suggest the potential of hydroalcoholic extract of C. ternatea for treatment of cognitive deficit in neurological disorders.

Treatment of depression, a common comorbidity in patients with epilepsy, is restricted as certain antidepressants are considered to be proconvulsants. In contrast, anticonvulsant effects have been reported with some antidepressants. In the present study, the effect of tianeptine, an antidepressant, was evaluated against pentylenetetrazole (PTZ)-induced seizures, cognitive impairment and oxidative stress in rats. Tianeptine was administered in three doses (20, 40 and 80 mg/kg) 30 min before PTZ (60 mg/kg, intraperitoneally). MK801, an N-methyl-D-aspartate antagonist, and naloxone, an opioid receptor antagonist, were administered with tianeptine to evaluate the involvement of N-methyl-D-aspartate and opioid receptors, respectively. Morris water maze, elevated plus maze and passive avoidance tests were performed for behavioural assessment. Brain malondialdehyde and reduced glutathione levels were estimated as markers of oxidative stress. Tianeptine showed dose-dependent protection against PTZ seizures. Coadministration of tianeptine with MK801 potentiated the anticonvulsant effect of tianeptine. The protective effect of tianeptine against PTZ seizures was mitigated when tianeptine was administered with naloxone. Impairment of learning and memory by PTZ was prevented by tianeptine. Tianeptine also attenuated the seizure-induced increased oxidative stress. Thus, tianeptine showed an anticonvulsant effect along with amelioration of seizure-induced cognitive impairment and oxidative stress. Hence, tianeptine could be a useful drug in epileptic patients with depression, with the advantage of having both antidepressant and antiepileptic effects.

This study aimed to compare the effects of β-sitosterol nanoparticles (BETNs) and β-sitosterol (BET) on cognitive impairment, oxidative stress, and inflammation in a myocardial infarction (MI) rat model using in silico and in vivo methods. β-Sitosterol (BET) and myeloperoxidase (MPO) ligand-receptor binding affinities were evaluated using Autodock Vina for docking and Gromacs for dynamics simulations. BET nanoparticles, prepared via solvent evaporation, had their size confirmed by a nanoparticle analyzer. ISO-induced cognitive impairment in rats was assessed through Morris water maze and Cook's pole climbing tests. Oxidative stress, inflammation, and cardiac injury were evaluated by measuring GSH, SOD, MDA, MPO, CkMB, LDH, lipid profiles, and ECGs. Histopathology of the CA1 hippocampus and myocardial tissue was performed using H&E staining. In silico analyses revealed strong binding affinities between BET and MPO, suggesting BET's potential anti-inflammatory effect. BETN (119.6 ± 42.6 nm; PDI: 0.809) significantly improved MI-induced cognitive dysfunction in rats (p < 0.001 ***), increased hippocampal GSH (p < 0.01 **) and SOD (p < 0.01 **) levels, and decreased hippocampal MDA (p < 0.05 *) and MPO levels (p < 0.01 **). BETNs also elevated cardiac GSH (p < 0.01 **) and SOD (p < 0.01 **) levels and reduced cardiac MPO (p < 0.01 **), CkMB (p < 0.001 **) and LDH (p < 0.001 **) levels. It restored lipid profiles, normalized ECG patterns, and improved histology in the hippocampal CA1 region and myocardium. Compared with BET treatment, BETNs were more effective in improving cognitive impairment, oxidative damage, and inflammation in MI rats, suggesting its potential in treating cognitive dysfunction and associated pathological changes in MI.

Glibenclamide mitigates cognitive impairment and hippocampal neuroinflammation in rats with type 2 diabetes and sporadic Alzheimer-like disease