Potential In Rats Research Articles

Pterocarpus soyauxii (Fabaceae) aqueous extract to prevent neuropsychiatric disorders associated with menopause by triggering ROS-dependent oxidative damage and inhibiting acetylcholinesterase, GABA-transaminase, and monoamine oxidase A: In vitro, in vivo, and in silico approaches

Pterocarpus soyauxii (PS) is traditionally used in Cameroon medicine to alleviate postmenopausal symptoms. Previous research has shown that it has tissue-selective potential and estrogen-mimetic effects on vaginal atrophy. Phytoestrogens like 7-O-acetyl formononetin, khrinone A, and 3′,5′-dimethoxy-4-stilbenol were found in its water extract by UHPLC, but there is no evidence of its effects on neurological disorders linked to post-menopause (ND-PO). The study aimed to investigate the phytochemical profile of PS aqueous extract, assess its neuroprotective potential in rats, and explore possible underlying pathways. We used colorimetric assays to study the phytochemical profile of PS extract. Effects of the extract on behavioral parameters, neuronal signaling, and integrity in an 84-day ovariectomized rat model. Molecular docking was performed to assess the ability of 7-O-acetyl formononetin, an isoflavone contained in PS, to cross the BBB and its binding affinity to the active sites of AChE, MAO-A, and GABA-T. Besides, the anti-AChE/BChE, antioxidant, and anti-inflammatory effects of PS were assessed by in vitro tests. PS aqueous extract contains polyphenols (656.58 ± 9.18 mgEAG/100gMS), flavonoids (201.25 ± 5.52 mgEQ/100gDW), and tannins (18.42 ± 1.25 mg/100gDW). It slows down anxiety, depressive disorders, cellular disorganization, and neuronal death in the hippocampus, dentate gyrus, and neocortex. In silico modeling was a powerful tool to assess the 7-O-acetylformononetin's ability to cross the BBB and strongly bind and inhibit AChE, MAO-A, and GABA-T. Thus, by combining GABAergic, cholinergic, and serotoninergic modulation, PS aqueous extract also possesses remarkable anti-AChE/BChE in vitro and induces antioxidant and anti-inflammatory potential in macrophages. Such estromimetics, antioxidant, anti-inflammatory, cholinergic, and monoaminergic modulators represent promising activities to develop neuroprotective drugs with optimal therapeutic profiles for menopausal women.

Effects of focal cortical cooling on somatosensory evoked potentials in rats

Although the focal brain cooling technique is widely used to examine brain function, the effects of cortical temperature at various levels on sensory information processing and neural mechanisms remain underexplored. To elucidate the mechanisms of temperature modulation in somatosensory processing, this study aimed to examine how P1 and N1 deflections of somatosensory evoked potentials (SEPs) depend on cortical temperature and how excitatory and inhibitory inputs contribute to this temperature dependency. SEPs were generated through electrical stimulation of the contralateral forepaw in anesthetized rats. The SEPs were recorded while cortical temperatures were altered between 17–38 °C either without any antagonists, with a gamma-aminobutyric acid type A (GABAA) receptor antagonist (gabazine), with an aminomethylphosphonic acid (AMPA) receptor antagonist (NBQX), or with an N-Methyl-D-aspartic acid (NMDA) receptor antagonist ([R]-CPP). The effects of different gabazine concentrations (0, 1, and 10 µM) were examined in the 35–38 °C range. The P1/N1 amplitudes and their peak-to-peak differences plotted against cortical temperature showed an inverted U relationship with a maximum at approximately 27.5 °C when no antagonists were administered. The negative correlation between these amplitudes and temperatures of ≥ 27.5 °C plateaued after gabazine administration, which occurred progressively as the gabazine concentration increased. In contrast, the correlation remained negative after the administration of NBQX and (R)-CPP. These results suggest that GABAergic inhibitory inputs contribute to the negative correlation between SEP amplitude and cortical temperature around the physiological cortical temperature.

LC-qTOF-MS/MS phytochemical profiling of Tabebuia impetiginosa (Mart. Ex DC.) Standl. leaf and assessment of its neuroprotective potential in rats

Ethnopharmacological relevanceTabebuia impetiginosa (Bignoniaceae) was traditionally used for memory enhancement and central nervous system (CNS) stimulation.Aim of the study: This study aims to create a metabolic profile of the ethyl acetate fraction of T. impetiginosa (TEF) and investigate for the first time its neuroprotective potential on cyclophosphamide (CP)-induced chemobrain, validating its traditional use. Materials and methodsMetabolite profiling of TEF was performed using Liquid Chromatography coupled with Quadrupole Time of Flight-Mass/Mass Spectrometry (LC-qTOF-MS/MS). For the in vivo study, CP (200 mg/kg, i.p.) was administered to induce cognitive impairment in rats; TEF (30 mg/kg, p.o.) was administered throughout the 14 days of the experiment to assess its role in mitigating CP-induced neuronal deficits. Behavioral tests including locomotor, Y-maze, and passive avoidance tests were conducted. Additionally, biochemical markers such as reduced glutathione (GSH), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), and caspase-3 immunoexpression were assessed in the hippocampus area. ResultsForty-four phytoconstituents were tentatively identified in TEF, mainly iridoids and organic acids. TEF showed significant memory enhancement as evidenced by the increase in step-through latency in the passive avoidance test by 1.5 folds and the increase in sequence alternation percentage (SAP) in the Y-maze test by 67.3%, as compared to CP-group. Moreover, it showed pronounced antioxidant and anti-inflammatory potentials evidenced by the significant elevation in reduced glutathione (GSH) levels by 80% and a pronounced decline in MDA and TNF-α levels by 24% and 45%, respectively relative to the CP group. TEF treatment restored normal hippocampal histological features and attenuated apoptotic caspase-3 expression by 70% compared to the CP group. ConclusionsTEF can act as a promising natural scaffold in managing the chemobrain induced by CP in cancer patients.

Local contribution to the somatosensory evoked potentials in rat's thalamus.

Local Field Potential (LFP), despite its name, often reflects remote activity. Depending on the orientation and synchrony of their sources, both oscillations and more complex waves may passively spread in brain tissue over long distances and be falsely interpreted as local activity at such distant recording sites. Here we show that the whisker-evoked potentials in the thalamic nuclei are of local origin up to around 6 ms post stimulus, but the later (7-15 ms) wave is overshadowed by a negative component reaching from cortex. This component can be analytically removed and local thalamic LFP can be recovered reliably using Current Source Density analysis. We used model-based kernel CSD (kCSD) method which allowed us to study the contribution of local and distant currents to LFP from rat thalamic nuclei and barrel cortex recorded with multiple, non-linear and non-regular multichannel probes. Importantly, we verified that concurrent recordings from the cortex are not essential for reliable thalamic CSD estimation. The proposed framework can be used to analyze LFP from other brain areas and has consequences for general LFP interpretation and analysis.

Novel Phytosomal Formulation of Emblica officinalis Extracts with Its In Vivo Nootropic Potential in Rats: Optimization and Development by Box-Behnken Design

Purpose. The present study aimed to improve the aqueous solubility, permeability, bioavailability, and nootropic potential of standardized Emblica officinalis extract (EOE) by developing a novel phytosomal formulation. Method. Emblica officinalis extract-loaded phytosomes (EOPs) were prepared using solvent evaporation. The EOP was prepared at different molar ratios of extract and phospholipid. Herein, the effects of phospholipid extract ratio (A), temperature (B), and reaction time (C) were systematically investigated on entrapment efficiency using Box-Behnken design. In vitro and in vivo characterizations of the optimized formulation were performed. Results. Optimized EOP formulation (89.90 ± 0.24 μg/ml) exhibited improved aqueous solubility than plain EOE (11.85 ± 0.25 μg/ml). The optimized formulation’s particle size and Zeta potential were 198.4 ± 0.20 nm and −39.0 ± 0.40 mv. DSC and XRD studies confirmed the partial amorphization of EOE in phytosomes. Optimized formulation exhibited 69.82 ± 0.17% of EOE release at 12 h and followed zero-order release kinetics. Moreover, the phytosomal formulation of EOE exhibited its rationality with an improvement of bioavailability by 2.7 folds compared with pure EOE. Compared to EOE, EOP showed significantly (p<0.05 lower escape and transfer latencies on both days in MWMT and EPMT, indicating more effective memory-enhancing activity. Furthermore, EOP-treated rats exhibited improved acetylcholine (Ach) levels than EOE. Brain tissue concentrations measured following EOP oral administration (1.06 ± 0.04 μg/ml) were substantially greater (p<0.05) than those following EOE (0.32 ± 0.07 μg/ml). The brain dopamine and serotonin concentration were found to be higher (16.27 ± 1.209 and 43.28 ± 1.550 ng/ml) in the EOP-treated group as compared to the pure extract-treated group (10.40 ± 1.185 and 32.79 ± 1.738 ng/ml). Conclusion. Improvement of aqueous solubility, permeability, dissolution, bioavailability, and narrower particle size distribution could facilitate enhancement in the nootropic potential of EOE phytosomal formulation.

Mechanistic insights into the hepatoprotective properties of Mallotus phillipensis fruit: Targeting proinflammatory cytokines and free radicals using isolated compound

Ethnopharmacological relevance:Mallotus phillipensis (MP) belongs to the endangered plants of great medicinal value. Widely used in the Ayurvedic healthcare system, parts of the plant which are rich in secondary metabolites are used in the treatment of several diseases like eczema, bronchitis, worm infestation, diabetes, kidney stones, cancer, and malaria. In ethnomedicine, MP has been reported to be traditionally used in the treatment and healing of jaundice and inflammatory conditions in the Ayurveda system. This plant was thus selected to explore its hepatoprotective activity. ObjectiveThis study was undertaken to investigate the protective property of MP and a flavanone i.e. 7,4′-Dihydroxy-3′′,3′′-dimethyl-(5,6-pyrano-2′′-one)-8′′′-(3′′′,3′′′-dimethylallyl)-flavanone (A4) previously identified and obtained from the same plant on CCl4-induced liver injury in animal models to validate the folkloric claims. Traditional medicinal plants have the potential to provide phytoconstituents capable of healing liver cells. In this regard, MP is used in various traditional medicinal systems to treat several diseases. Though it has been studied for its hepatoprotective potential, activity on the isolated compounds is yet to be reported to confirm the active principle. Therefore, the study assessed the hepatoprotective effect of ethyl acetate and methanol extracts and a flavanone isolated from MP fruit extract. MethodsMethanol and ethyl acetate fractions of MP fruits at two different doses (300 mg/kg and 500 mg/kg) and a flavanone (A4-50 mg/kg) isolated from MP were tested for hepatoprotective potential in rats. At 50 mg/kg dosage/ day orally, silymarin was used as a standard drug. The effect on liver enzymes and serum cytokines was also verified in animal models. Histopathology and antioxidant tests were performed on liver tissue. Elemental analysis, 1H- &13C NMR, MS, IR and UV spectral data were used to characterize the structure of isolated flavanone (A4). ResultsThe ethyl acetate and methanol fractions of MP fruit and the isolated compound A4 i.e. flavanone showed strong hepatoprotective effects, as evidenced by their ability to impede the rise in serum transaminases. They also decreased the serum IL-1, IL-6 and TNF-α levels and showed significant antioxidant potential. The effect was found to be in decreasing order as MEA 500 > MPM 500 > MEA 300 > A4 > MPM 300. ConclusionsThe results indicate that MP fruit fractions with methanol, ethyl acetate and A4 can lessen CCL4-induced liver damage. This may be because of their antioxidant and cytokine-inhibitory properties.

Effects of Acetyl-L-Carnitine Administration on Auditory Evoked Potentials in Rats Exposed to Chronic Ethanol

These days, one of the biggest issues facing public health is chronic alcohol consumption. Prolonged alcohol intake has been associated with a number of illnesses, including pancreatitis, cerebrovascular illnesses, and liver damage. It is known that the endogenous molecule acetyl-L-carnitine (ALCAR) has neuroprotective properties. The objective of this study was to examine the impact of ALCAR on auditory evoked potentials (AEP) in a model of chronic alcoholism in rats. Four groups (n = 10) were randomly formed from 40 three-month-old albino Wistar rats: Sham (Sh), chronic ethanol (CE), ALCAR administered (ALCAR), and chronic ethanol+ALCAR (CE+ALCAR). The rats were administered either distilled water, ethanol, ALCAR, or ethanol+ALCAR via gavage for a duration of 4 weeks. AEP recordings were acquired from each rat upon the conclusion of the experiment period. The amplitudes of P1N1 and N1P2, in addition to the latencies of the P1, N1, and P2 peaks, were analyzed. Our findings showed that P1, N1, and P2 latencies were considerably prolonged in the CE group compared to the Sh group. Furthermore, the amplitudes of P1N1 and N1P2 exhibited an increase in the CE group relative to the Sh group, a decline in the CE+ALCAR group in comparison to the CE group, and a subsequent return to normal levels. Finally, our results demonstrated that, at the dose and duration used here, ALCAR normalized the increased neuronal activity but had no effect on the conduction velocity of the hearing signal.

Discovery of novel NSAID hybrids as cPLA2/COX-2 dual inhibitors alleviating rheumatoid arthritis via inhibiting p38 MAPK pathway

A series of NSAIDs hybrid molecules were synthesized and characterized, and their ability to inhibit NO release in LPS-induced RAW264.7 macrophages was evaluated. Most of the compounds showed significant anti-inflammatory activity in vitro, of which (2E,6Z,9Z,12Z,15Z)-1,1,1-trifluorohenicosa-2,6,9,12,15-pentaen-2-yl 2-(4-benzoylphenyl) propanoate (VI-60) was the most optimal (IC50 = 3.85 ± 0.25 μΜ) and had no cytotoxicity. In addition, VI-60 notably reduced the production of PGE2 in LPS-stimulated RAW264.7 cells compared to ketoprofen. Futhur more, VI-60 significantly inhibited the expression of iNOS, cPLA2, and COX-2 and the phosphorylation of p38 MAPK in LPS-stimulated RAW264.7 cells. The binding of VI-60 to cPLA2 and COX-2 was directly verified by the CETSA technique. In vivo studies illustrated that VI-60 exerted an excellent therapeutic effect on adjuvant-induced arthritis in rats by regulating the balance between Th17 and Treg through inhibiting the p38 MAPK/cPLA2/COX-2/PGE2 pathway. Encouragingly, VI-60 showed a lower ulcerative potential in rats at a dose of 50 mg/kg compared to ketoprofen. In conclusion, the hybrid molecules of NSAIDs and trifluoromethyl enols are promising candidates worthy of further investigation for the treatment of inflammation, pain, and other symptoms in which cPLA2 and COX-2 play a role in their etiology.

Nrf2 enhances the therapeutic efficiency of adipose-derived stem cells in the treatment of neurogenic erectile dysfunction in a rat model

BackgroundErectile dysfunction (ED) caused by intraoperative nerve injury is a major complication of pelvic surgery. Adipose-derived stem cells (ADSCs) have presented therapeutic potential in a rat model of bilateral cavernous nerve injury (BCNI), while inadequate in vivo viability has largely limited their application. Nuclear factor-E2-related Factor (Nrf2) is a key transcription factor that regulates cellular anti-oxidative stress. In this work, we investigated the effect of Nrf2 expression regulation on the viability of ADSCs, and explore its repair potential in a BCNI rat model.ResultsThe survival time of tert-Butylhydroquinone (tBHQ)-ADSCs in BCNI model increased obviously. In addition, the tBHQ-ADSCs group presented better restoration of major pelvic ganglion (MPG) nerve contents and fibers, better improvement of erectile function, and less penile fibrosis than the other groups. Moreover, the expression of Nrf2 and superoxide dismutase 1 (SOD1) were higher than those of other groups.ConclusionNrf2 could enhance the anti-oxidative stress ability of ADSCs, so as to improve the therapeutic effect of ADSCs on BCNI rat model.

In Vivo and in Silico Based Evaluation of Antidiabetic Potential of an Isolated Flavonoid from Allium hookeri in Type 2 Diabetic Rat Model.

Allium hookeri (F: Liliaceae), an indigenous plant of Manipur, India, is traditionally used to treat various diseases and disorders like diabetes, hypertension, and stomach ache. In our previous study, the methanol extract of the plant showed significant antidiabetic potential in rats. In the present study, we evaluated the antidiabetic potential of a flavonoid compound named MEA isolated from the methanolic leaf extract of A. Hookeri in rats. Additionally, we assessed the compound's mode of action through the molecular docking study. The MEA reduced the blood glucose level from 317±12.8 to 99.4±6.67 mg/dl after 21 days of treatment. Besides, MEA also restored the body weights and other biochemical parameters including lipid profile significantly compared to the diabetic group (p<0.001). The histoarchitecture of the pancreatic tissues of the MEA treated group was also improved compared to the diabetic group. In the docking study, the compound showed good binding affinity in the active binding site of the two structures of pancreatic beta-cell SUR1 (Sulfonylurea Receptor 1) subunit with CDocker energy -31.556 kcal/mol and -39.703 kcal/mol, respectively. The compound MEA was found to be drug-like with non-carcinogenic, non-mutagenic and non-irritant properties. These findings indicate the antidiabetic potential of MEA, which might act by modulating the pancreatic beta-cell SUR1 subunit present in the KATP channel. Hence, the MEA would be a promising lead molecule to develop new antidiabetic drug candidates of the future.

Abuse potential assessment of the dual orexin receptor antagonist daridorexant in rats.

Drugs that act on the central nervous system (CNS) and have sedative effects can lead to abuse in humans. New CNS-active drugs often require evaluation of their abuse potential in dedicated animal models before marketing approval. Daridorexant is a new dual orexin receptor antagonist (DORA) with sleep-promoting properties in animals and humans. It was approved in 2022 in the United States and Europe for the treatment of insomnia disorder. Nonclinical evaluation of abuse potential of daridorexant using three specific rat models assessing reinforcement, interoception, and withdrawal. Reinforcing effects of daridorexant were assessed in an operant rat model of intravenous drug self-administration. Similarity of interoceptive effects to those of the commonly used sleep medication zolpidem was tested in an operant drug discrimination task. Withdrawal signs indicative of physical dependence were evaluated upon sudden termination of chronic daridorexant treatment. Rat experiments were conducted at a dose range resulting in daridorexant plasma concentrations equaling or exceeding those achieved at the clinically recommended dose of 50 mg in humans. Daridorexant had no reinforcing effects, was dissimilar to zolpidem in the drug discrimination task, and did not induce any withdrawal-related signs upon treatment discontinuation that would be indicative of physical dependence. Daridorexant showed no signs of abuse or dependence potential in rats. Our data indicate that daridorexant, like other DORAs, has a low potential for abuse in humans.

Hippocratea africana root extract and fractions attenuate paracetamol-induced oxidative stress and kidney injuries in rats

Hippocratea africana root used locally in the treatment of poisoning was investigated to confirm its antidotal potential in rats. The root extract (200-600 mg/kg) and fractions; dichloromethane (DCM) and aqueous, 400 mg/kg) were evaluated for nephroprotective activity against paracetamol-induced kidney injury in rats. Anti-oxidative stress and renoprotective potentials of root extract and fractions were assessed by determining oxidative stress markers levels, kidney function parameters and histopathology in rats. The root extract and fractions caused significant (p&lt;0.05 – 0.001) increases in the levels of oxidative stress markers (SOD, CAT, GPx, GSH) in the kidney, while MDA level was decreased. The root extract/fractions caused significant (p&lt;0.05-0.001) reduction of elevated serum levels of creatinine and urea of the rats, while the electrolytes levels were considerably reduced though not significant. Histology of kidney revealed absence or significant reductions in pathological features in the treated rats compared to paracetamol treated group group. The results show that the root extract and fractions of H.africana have antioxidative stress and nephroprotective potentials which may be due to the antioxidant activities of their phytochemical constituents.

Nephroprotective Activities of Ethanol Root Extract and Fractions of Hippocratea africana Against Doxorubicin-Induced Kidney Toxicity

Hippocratea africana root used locally in the treatment of poisoning was investigated to confirm its antidotal potential in rats. The root extract (200-600 mg/kg) and fractions; dichloromethane (DCM) and aqueous, 400 mg/kg) were evaluated for nephroprotective activity against doxorubicin-induced kidney injury in rats. Kidney function parameters, kidney oxidative stress markers and kidney histology were used to assess the kidney protective effect of the extract. The root extract and fractions (200-600 mg/kg) significantly (p&lt;0.05-0.01) reduced the levels of creatinine, urea and electrolytes that were elevated by doxorubicin. Also, the MDA level elevated by doxorubicin was reduced by the extract and fractions co-administration, while the levels of GSH, GST, SOD, GPx, and CAT that were decreased by doxorubicin were significantly (p&lt;0.01) elevated by the root extract/fractions. Histology of the kidney sections of extract/fractions -treated animals showed reductions in the pathological features compared to the organotoxic-treated animals. The chemical pathological changes were consistent with histopathological observations suggesting marked nephroprotective potential. The anti-toxic effect of this plant may in part be mediated through the chemical constituents of the plant. The plant, Hippocratea africana possesses anti-toxicant properties which can be exploited in the treatment of doxorubicin related toxicities.

Omega-3 fatty acid-based self-microemulsifying drug delivery system (SMEDDS) of pioglitazone: Optimization, in vitro and in vivo studies

Pioglitazone (PGL) is an effective insulin sensitizer, however, side effects such as accumulation of subcutaneous fat, edema, and weight gain as well as poor oral bioavailability limit its therapeutic potential for oral delivery. Recent studies have shown that combination of both, PGL and fish oil significantly reduce fasting plasma glucose,improve insulin resistance, and mitigate pioglitazone-induced subcutaneous fat accumulation and weight gain. Nevertheless, developing an effective oral drug delivery system for administration of both medications have not been explored yet. Thus, this study aimed to develop a self-micro emulsifying drug delivery system (SMEDDS) for the simultaneous oral administration of PGL and fish oil. SMEDDS was developed using concentrated fish oil,Tween® 80, and Transcutol HP and optimized by central composite design (CCD). The reconstituted, optimized PGL-SMEDDS exhibited a globule size of 142 nm, a PDI of 0.232, and a zeta potential of −20.9 mV. The in-vitro drug release study of the PGL-SMEDDS showed a first-order model kinetic release and demonstrated remarkable 15-fold enhancement compared to PGL suspension. Additionally, following oral administration in fasting albino Wistar rats, PGL-SMEDDS exhibited 3.4-fold and 1.4-fold enhancements in the AUC0–24h compared to PGL suspension and PGL marketed product. The accelerated stability testing showed that the optimized SMEDDS formulation was stable over a three-month storage period. Taken together, our findings demonstrate that the developed fish oil-based SMEDDS for PGL could serve as effective nanoplatforms for the oral delivery of PGL, warranting future studies to explore its synergistic therapeutic potential in rats.

Effects of different doses of dopamine receptor agonist pramipexole on neurobehaviors and changes of mitochondrial membrane potentials in rats with global cerebral ischemia-reperfusion injury

ObjectiveTo explore the effects of different doses of dopamine receptor agonist pramipexole on neurobehaviors and changes of mitochondrial membrane potential in rats with global cerebral ischemia-reperfusion injury. MethodsA total of 75 SPF Sprague-Dawley male rats were randomly divided into sham group (n=20), model group (n=20), pramipexole administration group (n=35). The rat model of global cerebral ischemia-reperfusion injury was prepared by the modified Pulsinelli's four-vessel occlusion method. Pramipexole administration group was administered intraperitoneally in rats with global cerebral ischemia-reperfusion injury at different doses of pramipexole 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, once a day for 14 consecutive days. Based on the results of modified neurological severity scores, open field test and morphology by Nissl's staining to determine the optimal dose of pramipexole. Mitochondrial membrane potential in the optimal dose of pramipexole administration group were measured by the JC-1 fluorescent probe staining method. Results1. Different doses of pramipexole 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, and 2 mg/kg, were used as drug administration in rats with global cerebral ischemia-reperfusion injury for 14 consecutive days, and we found that all four doses of pramipexole could improve the modified neurological severity scores of rats with global cerebral ischemia-reperfusion injury to varying degrees, but only 0.5 mg/kg pramipexole at 1, 3, 7 and 14 days consistently reduced modified neurological severity scores and improved neurological function in rats with global cerebral ischemia-reperfusion injury. In the open-field test, only 0.5 mg/kg pramipexole increased the number of entries into the central zone, duration spent in the central zone, total distance travelled in the open field and average velocity, which improved the spontaneous activities and reduced anxiety and depression of rats with global cerebral ischemia-reperfusion injury. 2. Different doses of pramipexole 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, and 2 mg/kg for 14 consecutive days significantly increased the number of surviving neurons in the hippocampal CA1 subfield in rats with global cerebral ischemia-reperfusion injury to varying degrees. Based on these results, we tentatively found that 0.5 mg/kg pramipexole may be the optimal dose in all of the above. 3. We found that 0.5 mg/kg pramipexole significantly increased the mitochondrial membrane potential in rats after global cerebral ischemia-reperfusion injury. ConclusionDifferent doses of dopamine receptor agonist pramipexole improved neurological function of rats with global cerebral ischemia-reperfusion injury to varying degrees, and 0.5 mg/kg pramipexole may be the optimal dose in all of the above. Pramipexole may produce neuroprotective effects by protecting neurons in the hippocampus and improving the mitochondrial membrane potential after global cerebral ischemia-reperfusion injury.

LC-MS/MS and GC/MS Profiling of Petroselinum sativum Hoffm. and Its Topical Application on Burn Wound Healing and Related Analgesic Potential in Rats.

Parsley (Petroselinum sativum Hoffm.) is renowned for its ethnomedicinal uses including managing pain, wound, and dermal diseases. We previously highlighted the estrogenic and anti-inflammatory properties of parsley and profiled the phytochemistry of its polyphenolic fraction using HPLC-DAD. To extend our investigation, we here characterized the phytochemical composition of the hydro-ethanolic extract using LC-MS/MS and GC-MS upon silylation, and evaluated the antioxidant, analgesic, antimicrobial, and wound healing activities of its hydro-ethanolic and polyphenolic fraction. The antioxidant property was assessed using FRAP, DPPH, and TAC assays. The antimicrobial activity was tested against four wound infectious microbes (Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans). The analgesic effect was studied using acetic acid (counting the number of writhes) and formalin (recording the licking and biting times) injections while the wound healing activity was evaluated using burn model in vivo. The LC-MS/MS showed that the hydro-ethanolic contains four polyphenols (oleuropein, arbutin, myricetin, and naringin) while GC-MS revealed that it contains 20 compounds including malic acid, D-glucose, and galactofuranoside. The hydro-ethanolic (1000 mg/kg) decreased abdominal writhes (38.96%) and licking time (37.34%). It also elicited a strong antioxidant activity using DPPH method (IC50 = 19.38 ± 0.15 µg/mL). Polyphenols exhibited a good antimicrobial effect (MIC = 3.125-12.5 mg/mL). Moreover, both extracts showed high wound contraction by 97.17% and 94.98%, respectively. This study provides evidence that P. sativum could serve as a source of bio-compounds exhibiting analgesic effect and their promising application in mitigating ROS-related disorders, impeding wound infections, and enhancing burn healing.

Embryo-fetal safety evaluation of ondansetron in rats.

Ondansetron is a 5HT3 receptor antagonist, used to mitigate the effects of nausea and vomiting after chemotherapy or surgery. Since nausea and vomiting are common experiences during the first trimester of pregnancy, this antiemetic has been the main drug used during this period. To evaluate the effects of ondansetron on the embryo-fetal development, which are still very contradictory, pregnant rats were exposed to therapeutic doses of ondansetron (1.7 or 2.5 mg/kg) daily, from gestational day (GD) 6 to 15. No clinical signs of toxicity were observed in dams during the treatment. Although the hemato-biochemical parameters were similar among the groups, histological changes, as well as a reduction in the weight of kidney were found in the treated dams. After fetal examination, no visceral and skeletal abnormalities were observed in treated fetuses. In conclusion, therapeutic doses of ondansetron have low teratogenic potential in rats. These data provide important information about the drug safety during pregnancy.

Fenchone, a monoterpene: Toxicity and diuretic profiling in rats.

Fenchone is a monoterpene present in the essential oils of various plants, including Foeniculum vulgare and Peumus boldus. Previous studies confirmed the anti-inflammatory, antioxidant, wound-healing, antidiarrheal, antifungal, antinociceptive, and bronchodilator activities of fenchone. Owing to various pharmacological activities of Fenchone, the current research was designed to evaluate its diuretic activity along with toxicity profiling. For evaluating acute toxicity, OECD guideline 425 was followed in which a single dose of 2000mg/kg was orally administered to rats. For evaluating the diuretic potential in rats, three doses of Fenchone (100, 200, and 400mg/kg) were assayed in comparison to furosemide (15mg/kg) as the standard drug, followed by measurements of urinary volume, urinary electrolytes, uric acid, and urinary creatinine in saline-loaded rats for 8h. The acute toxicity study showed a significant increase in hemoglobin (Hb), red blood cells (RBCs), alkaline phosphatase (ALP), and alkaline transaminase (ALT) along with a significant decrease in serum triglycerides, cholesterol, and uric acid levels when compared with the control group. The oxidative stress parameter, superoxide dismutase (SOD), was increased in the heart and spleen. Nitrite (NO) and glutathione were significantly increased in the kidney. The acute diuretic effect of Fenchone (400mg/kg) significantly increased the urinary output, electrolytes (Na+, K+, and Ca++), urinary creatinine, and urinary uric acid in a dose-dependent manner. The Na+/K+ ratio was remarkably higher in the treatment group than that of the control group. The diuretic index, saluretic index, and Lipschitz value were also calculated from electrolyte concentration and urinary volume measurements, and the values were significantly increased in rats administered with fenchone at 400mg/kg dose. The current study concluded that fenchone is safe and has remarkable diuretic action.

Behaviourally modulated hippocampal theta oscillations in the ferret persist during both locomotion and immobility

Theta oscillations are a hallmark of hippocampal activity across mammals and play a critical role in many hippocampal models of memory and spatial navigation. To reconcile the cross-species differences observed in the presence and properties of theta, we recorded hippocampal local field potentials in rats and ferrets during auditory and visual localisation tasks designed to vary locomotion and sensory attention. Here, we show that theta oscillations occur during locomotion in both ferrets and rats, however during periods of immobility, theta oscillations persist in the ferret, contrasting starkly with the switch to large irregular activity (LIA) in the rat. Theta during immobility in the ferret is identified as analogous to Type 2 theta that has been observed in rodents due to its sensitivity to atropine, and is modulated by behavioural state with the strongest theta observed during reward epochs. These results demonstrate that even under similar behavioural conditions, differences exist between species in the relationship between theta and behavioural state.

The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α1-Adrenolytic Properties.

Heart rhythm abnormalities are a cause of many deaths worldwide. Unfortunately, the available antiarrhythmic drugs show limited efficacy and proarrhythmic potential. Thus, efforts should be made to search for new, more effective, and safer pharmacotherapies. Several studies suggested that blocking the α1-adrenoceptors could restore normal heart rhythm in arrhythmia. In this study, we aimed to assess the antiarrhythmic potential of S-61 and S-73, two novel pyrrolidin-2-one derivatives with high affinity for α1-adrenergic receptors. First, using radioligand binding studies, we demonstrated that S-61 and S-73 did not bind with β1-adrenoceptors. Next, we assessed whether S-61 and S-73 could protect rats against arrhythmia in adrenaline-, calcium chloride- and aconitine-induced arrhythmia models. Both compounds showed potent prophylactic antiarrhythmic properties in the adrenaline-induced arrhythmia model, but the effect of S-61 was more pronounced. None of the compounds displayed antiarrhythmic effects in calcium chloride- or aconitine-induced arrhythmia models. Interestingly, both derivatives revealed therapeutic antiarrhythmic activity in the adrenaline-induced arrhythmia, diminishing heart rhythm irregularities. Neither S-61 nor S-73 showed proarrhythmic potential in rats. Finally, the compounds decreased blood pressure in rodents. The hypotensive effects were not observed after coadministration with methoxamine, which suggests the α1-adrenolytic properties of both compounds. Our results confirm that pyrrolidin-2-one derivatives possess potent antiarrhythmic properties. Given the promising results of our experiments, further studies on pyrrolidin-2-one derivatives might result in the development of a new class of antiarrhythmic drugs.