Exploring the neuropharmacological potential of empagliflozin on nootropic and scopolamine-induced amnesic model of Alzheimer's like conditions in rats.

BACKGROUND: Alzheimer's disease (AD) is one of the most challenging and prevalent neurodegenerative disorder globally with a rising prevalence, characterized by progressive cognitive decline, memory loss, and behavioural changes. Current research aims to determine the nootropic and anti-amnesic effect of Empagliflozin (EMPA) against scopolamine-induced amnesia in rats, by modulating the cholinergic and N-Methyl D-Aspartate (NMDA) receptors. METHODS: Rats were treated once daily with an EMPA (5 and 10 mg/kg) and donepezil (2.5 mg/kg) for successive 26 days. During the final 13 days of treatment, a daily injection of scopolamine (1 mg/kg) was administered to induce cognitive deficits. RESULTS: EMPA was found to be significantly reduce escape latency, increase time spent in the target quadrant, and enhanced the number of target zone crossings in the Morris water maze (MWM) test, indicating improved spatial memory. Moreover, EMPA increased the recognition index and the number of spontaneous alternations in the novel object recognition (NOR) and Y-maze tests, respectively, suggesting enhanced memory. DISCUSSION: Interestingly doses of EMPA (5 mg/kg, 10 mg/kg) exhibited memory-enhancing effects even in the absence of scopolamine-induced impairment. Biochemical analysis revealed that EMPA elevated the levels of glutathione (GSH), a potent antioxidant, while decreasing lipid peroxidation (LPO) activity and increasing catalase (CAT) levels, indicating its antioxidative properties. Interestingly molecular docking studies revealed that EMPA fit perfectly in the active sites of M1 muscarinic acetylcholine (mACh) and NMDA receptors. These results indicated that the nootropic and antiamnesic effect of EMPA is possibly mediated via M1 and NMDA receptors and might be a remedy for AD.

Possible involvement of GABAergic system on central amygdala Mediated anxiolytic effect of agmatine in rats.

OBJECTIVES: To study the pharmacological interactions between agmatine and gamma aminobutyric acid (GABA) modulatory agents in the regulation of anxiety-like behavior in rats. MATERIALS AND METHODS: Male Wistar rats were treated drugs per se or in combination and 15 min after last injection were subjected to elevated plus-maze (EPM) test. Anxiety-like behavior was evaluated by measuring behavioral conventional readout, open arm activity (duration and/or entries) for 5-minute duration. RESULTS: Acute intra-central amygdala (CeA) injection of agmatine (0.1-0.6 µmol/site/rat), muscimol (0.25-1 nmol/site/rat), diazepam (5-20 µg/site/rat) and allopregnanolone (2-8 µg/site/rat) increased open arm entries of the rats in EPM suggesting anxiolytic effect in dose dependent manner. Moreover, the anxiolytic effect at subeffective dose of agmatine (0.1 µmol/site/rat) was potentiated by subeffective dose of muscimol (0.25 nmol/site/rat), diazepam (5 µg/site/rat) and allopregnanolone (4 µg/site/rat). Whereas, pretreatment with GABAA receptor antagonist, bicuculline (10 ng/site/rat) blocked the anxiolytic effect of agmatine and its synergistic effect of agmatine plus muscimol. Similarly, benzodiazepine (BZD) receptor antagonist, flumazenil (15 µg/site/rat) and GABA allosteric modulator antagonist, RO 15-45 13 (10 µg/site/rat) reduced the anxiolytic effect of agmatine, given alone and with diazepam and allopregnanolone, respectively. CONCLUSION: These results indicated that anxiolytic effect of agmatine is medicated via GABAergic mechanisms, probably conciliated by the GABAA receptor subtypes. Modulation of interplay between agmatine and GABAA receptor activity might be a pertinent solution for the regulation of anxiety.

Tailoring Deep Eutectic Solvents to Provoke Solubility and Bioavailability of Naringin: Implications of a Computational Approach.

Recently, the applications of deep eutectic solvents (DESs) as green and sustainable solvents for the solubilization of functional foods and phytophenols have dramatically risen concerning global issues on the utilization of organic solvents. Nevertheless, developing a suitable DES system for phytocomponents to enhance its solubility and bioavailability is complex and requires a sound experimental setup. Herein, we have attempted to develop DES encompassing the choline chloride (ChCl) along with oxalic acid (OA), l-glutamine (l-Glu), urea (U), and glycerol (Gro) at different ratios to elicit the solubility and bioavailability of naringin (NAR). Several DES systems were designed and tested for solubility, kinematic viscosity, and pH. Among these, DES-NAR encompassing ChCl/Gro in a 1:3 ratio exhibited the maximum solubility of NAR (232.56 ± 7.1 mg/mL) and neutral characteristic and thus considered suitable for NAR. Further, the conductor-like screening model for real solvents (COSMO-RS) has been employed to estimate the molecular and electrostatic interactions. DES-NAR was evaluated by polarized optical microscopy, Fourier-transform infrared (FTIR), differential scanning calorimetry (DSC), and 1H NMR to investigate the molecular transition and interaction. Further, diffusion and permeability studies were performed, which suggest significant improvements in DES-NAR. Likewise, the pharmacokinetic studies revealed a two times increase in the oral bioavailability of NAR in a designed DES system. Thus, the work represents a systematic and efficient development of the DES system for a potential phytocomponent considering the biosafety impact, which may widen the interest in pharmaceutical and food sciences.

Reversal of lipopolysaccharide-induced learning and memory deficits by agmatine in mice.

MATERIALS AND METHODS: Learning and memory functions in animals were evaluated by using Novel object recognition (NOR) and Morris water maze (MWM) tests. Following 7 days of LPS administration, animals were subjected to NOR test on Day-8 and MWM test on Days-9 to 13 for the assessment of recognition and spatial learning and memory, respectively. RESULTS: LPS administration produced significant deficits in recognition and spatial memory in mice after seven days of LPS administration. In LPS pre-treated mice, agmatine treatment on Day-8 resulted in the increased exploration to the novel object. Agmatine treatment (Day 8-12) in mice showed reduction in the escape latency and time spent in the target quadrant (probe trial) in the MWM test. However, co-administration of agmatine with LPS in mice for 7 days showed higher discrimination index in NOR test on Day-8. This co-administration also decreased escape latency and time spent in the target quadrant in MWM test on Days 9-13 as compared to LPS control group. CONCLUSION: Results implies the protective and curative effects of agmatine against LPS-induced loss of memory functions in experimental animals.HighlightsSubchronic but not acute lipopolysaccharides induce memory deficitsLipopolysaccharides impairs recognition and spatial memory in mice.Agmatine prevents lipopolysaccharides-induced loss of memory.Agmatine reverses deficits in learning and memory by lipopolysaccharides.

Development and statistical optimization of alginate-Neusilin US2 micro-composite beads to elicit gastric stability and sustained action of hesperidin.

The Alginate-Neusilin US2 micro-composite (MC) beads were fabricated and optimized for oral delivery of hesperidin (HES). A 32 full factorial design encompassing independent variables (factors) such as the concentration of sodium alginate (X1), and Neusilin US2 (X2) and dependant variables (response) such as particle size (Y1), entrapment efficiency (Y2), and swelling degree (Y3). Nine batches were prepared by formulation design employing statistical software JMP 13.2.1. The multiple regression analysis (MLRA) was carried to explore the influence of factor over responses. Further, a prediction profiler was used to trace the optimum concentration of factors based on desirable responses. The optimized beads (OF) were characterized for their morphology and size by motic microscopy and scanning electron microscopy. In vitro release, kinetic studies were performed in simulated gastric and intestinal fluids. In vivo pharmacokinetic studies revealed better absorption of HES from optimized beads (OF) compared to HES suspension which could be due to the prevention of acidic degradation of HES in the stomach. The estimated shelf life of OF formulation was found to be 3.86 years suggested better stability after fabrication. In a nutshell, the developed micro-composite beads of HES could be a better alternative for promising oral sustained delivery of HES.