Potential role of oxytocin in the regulation of memories and treatment of memory disorders.

Oxytocin (OXT) is an "affiliative" hormone or neurohormone or neuropeptide consists of nine amino acids, synthesized in magnocellular neurons of paraventricular (PVN) and supraoptic nuclei (SON) of hypothalamus. OXT receptors are widely distributed in various region of brain and OXT has been shown to regulate various social and nonsocial behavior. Hippocampus is the main region which regulates the learning and memory. Hippocampus particularly regulates the acquisition of new memories and retention of acquired memories. OXT has been shown to regulate the synaptic plasticity, neurogenesis, and consolidation of memories. Further, findings from both preclinical and clinical studies have suggested that the OXT treatment improves performance in memory related task. Various trials have suggested the positive impact of intranasal OXT in the dementia patients. However, these studies are limited in number. In the present study authors have highlighted the role of OXT in the formation and retrieval of memories. Further, the study demonstrated the outcome of OXT treatment in various memory and related disorders.

Therapeutic potential of vasopressin in the treatment of neurological disorders.

Vasopressin (VP) is a nonapeptide made of nine amino acids synthesized by the hypothalamus and released by the pituitary gland. VP acts as a neurohormone, neuropeptide and neuromodulator and plays an important role in the regulation of water balance, osmolarity, blood pressure, body temperature, stress response, emotional challenges, etc. Traditionally VP is known to regulate the osmolarity and tonicity. VP and its receptors are widely expressed in the various region of the brain including cortex, hippocampus, basal forebrain, amygdala, etc. VP has been shown to modulate the behavior, stress response, circadian rhythm, cerebral blood flow, learning and memory, etc. The potential role of VP in the regulation of these neurological functions have suggested the therapeutic importance of VP and its analogues in the management of neurological disorders. Further, different VP analogues have been developed across the world with different pharmacotherapeutic potential. In the present work authors highlighted the therapeutic potential of VP and its analogues in the treatment and management of various neurological disorders.

Hypoglycemia and anxiolysis mediated by levofloxacin treatment in diabetic rats.

Purpose: The present study was designed to determine the effect of levofloxacin (LVX) treatment on the blood glucose level, insulin sensitivity, anxiety level, nitrite and MDA level of STZ induced diabetic rats. Methods: Wistar rats were used in the present study. The rats were made diabetic by the administration of single dose of STZ (45 mg/kg, i.p.) and NAD (50 mg/kg, i.p.). The rats with the blood glucose level greater than 200 mg/dl were considered as diabetic (confirmed at day-3 of STZ-NAD administration). The non-diabetic rats were considered as control and received saline.Diabetic rats received metformin (50 mg/kg, p.o.) and LVX (20, 25, 30 and 35 mg/kg, i.p.) daily for 14 days (starting from the day at which STZ was injected). Following administration on 14th day,the blood sample was collected and the rats were subjected to behavioral assays for the determination of locomotor activity and anxiety level. Plasma was separated and used for the estimation ofnitrite and malondialdehyde (MDA)level. On 15th day OGTT was performed in the overnight fasted rats for the assessment of insulin sensitivity. Results: The results obtained suggested that the administration of STZ-NAD induced the hyperglycemia at day-3 of administration. Diabetic rats displayed the significant increase in blood glucose, anxiety related behavior, MDA level while significant decrease in the insulin sensitivity and plasma nitrite level. Daily administration of metformin to the diabetic rats decreased the blood glucose level, increased the time spent at the center of open field, reversed the anxiety related behavior in LDT and EPM, did not affect the plasma nitrite level, decreased the plasma MDA level, decreased the fasting glucose level and AUC in OGTT assay. LVX (30 and 35 mg/kg) treatment significantly decreased the blood glucose level of diabetic rats. LVX (20, 25 and 30 mg/kg) treatment significantly decreased the number of square crossing while LVX (20, 25, 30 and 35) treatment significantly increased the time spent at the center of the field by the diabetic rats. LVX (20 and 35 mg/kg) treatment significantly reversed the STZ induced anxiety in LDT while LVX (20, 30 and 35 mg/kg) treatment significantly reversed the STZ induced anxiety in EPM test. LVX (20, 25 and 35 mg/kg) treatment significantly increased the plasma nitrite level and LVX (20-35 mg/kg) treatment significantly decreased the MDA level of diabetic rats. Further only LVX (35 mg/kg) treatment significantly decreased the fasting glucose level and increased the AUC of diabetic rats. Conclusion: In conclusion, STZ-NAD administration increased the blood glucose level, anxiety related behavior, decreased the plasma nitrite and increased the MDA level. LVX administration potentiated the diabetogenic effects of STZ-NAD in rats. Daily administration of LVX decreased the blood glucose level of diabetic rats. LVX administration alleviated the STZ induced anxiety in OFT, LDT and EPM test. LVX administration increased the plasma nitrite level and decreased the lipid peroxidation in diabetic rats. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01234-0.

Therapeutic Potential of Myricetin in the Treatment of Neurological, Neuropsychiatric, and Neurodegenerative Disorders.

Myricetin (MC), 3,5,7,3',4',5'-hexahydroxyflavone, chemically belongs to a flavonoid category known to confer antioxidant, antimicrobial, antidiabetic, and neuroprotective effects. MC is known to suppress the generation of Reactive Oxygen Species (ROS), lipid peroxidation (MDA), and inflammatory markers. It has been reported to improve insulin function in the human brain and periphery. Besides this, it modulates several neurochemicals including glutamate, GABA, serotonin, etc. MC has been shown to reduce the expression of the enzyme Mono Amine Oxidase (MAO), which is responsible for the metabolism of monoamines. MC treatment reduces levels of plasma corticosterone and restores hippocampal BDNF (full form) protein in stressed animals. Further, MC has shown its protective effect against amyloid-beta, MPTP, rotenone, 6-OHDA, etc. suggesting its potential role against neurodegenerative disorders. The aim of the present review is to highlight the therapeutic potential of MC in the treatment of several neurological, neuropsychiatric, and neurodegenerative disorders.

Possible involvement of NO-cGMP signaling in the antidepressant like Effect of Amantadine in mice.

In the present study, antidepressant like effect of amantadine was studied in mice using tail suspension test (TST) and forced swim test (FST). Further the effect of amantadine treatment on the brain nitrite, glutamate and serotonin levels was also determined. Amantadine (AMT) (50, 100 and 150 mg/kg, i.p.) was administered to the mice and after 30 min of administration the mice were subjected to TST and FST. It was observed that the administration of AMT (100 and 150 mg/kg, i.p.) decreased the immobility period of mice in TST and FST significantly as compared to control. The findings from the whole brain neurochemical assay suggested that the AMT (100 and 150 mg/kg, i.p.) treatment decreased the brain nitrite and glutamate level but increased the brain serotonin significantly as compared to control. Further the influence of NO-cGMP signaling in the antidepressant like effect of amantadine was also determined. It was observed that the NO donor (i.e. L-Arginine (50 mg/kg, i.p.)) potentiated the effect elicited by AMT (50 mg/kg, i.p.) in FST and decreased the brain serotonin level of AMT (50 mg/kg, i.p.) treated mice. Further the pretreatment of cGMP modulator (i.e. Sildenafil (1 mg/kg, i.p.)) potentiated the behavioral effect elicited by AMT (50 mg/kg, i.p.) in TST and FST and decreased the brain nitrite and glutamate level of AMT (50 mg/kg, i.p.) treated mice. In conclusion, amantadine exerted antidepressant like effect in mice and NO-cGMP signaling influences the antidepressant like effect of amantadine in mice.

Delineation of Neuroprotective Effects and Possible Benefits of AntioxidantsTherapy for the Treatment of Alzheimer's Diseases by Targeting Mitochondrial-Derived Reactive Oxygen Species: Bench to Bedside.

Alzheimer's disease (AD) is considered the sixth leading cause of death in elderly patients and is characterized by progressive neuronal degeneration and impairment in memory, language, etc. AD is characterized by the deposition of senile plaque, accumulation of fibrils, and neurofibrillary tangles (NFTs) which are responsible for neuronal degeneration. Amyloid-ß (Aß) plays a key role in the process of neuronal degeneration in the case of AD. It has been reported that Aß is responsible for the production of reactive oxygen species (ROS), depletion of endogenous antioxidants, increase in intracellular Ca2+ which further increases mitochondria dysfunctions, oxidative stress, release of pro-apoptotic factors, neuronal apoptosis, etc. Thus, oxidative stress plays a key role in the pathogenesis of AD. Antioxidants are compounds that have the ability to counteract the oxidative damage conferred by ROS. Therefore, the antioxidant therapy may provide benefits and halt the progress of AD to advance stages by counteracting neuronal degeneration. However, despite the beneficial effects imposed by the antioxidants, the findings from the clinical studies suggested inconsistent results which might be due to poor study design, selection of the wrong antioxidant, inability of the molecule to cross the blood-brain barrier (BBB), treatment in the advanced state of disease, etc. The present review insights into the neuroprotective effects and limitations of the antioxidant therapy for the treatment of AD by targeting mitochondrial-derived ROS. This particular article will certainly help the researchers to search new avenues for the treatment of AD by utilizing mitochondrial-derived ROS-targeted antioxidant therapies.

Possible involvement of NO-sGC-cGMP signaling in the antidepressant like effect of pyridoxine in mice.

The present study was designed to determine the antidepressant like effect of pyridoxine in mice. Pyridoxine (12.5, 25 and 50 mg/kg, i.p.) was administered to the mice and depression related behavioral and neurochemical alterations were determined. It was observed that pyridoxine (50 mg/kg, i.p.) treatment decreased the immobility period in tail suspension test (TST) and forced swim test (FST) significantly as compared to control. Pyridoxine (50 mg/kg, i.p.) treatment increased the level of serotonin (5-HT) and decreased the level of nitrite in the brain of mice significantly as compared to control. Pyridoxine thus confer antidepressant like effect by increasing the level of 5-HT and by decreasing the level of nitrite in the brain of mice. Further the influence of nitric oxide (NO)/ soluble guanylate cyclase (sGC)/ cyclic guanosine monophosphate (cGMP) in antidepressant-like effect of pyridoxine was studied. It was observed that the pretreatment of NO donor (i.e. L-Arginine) and cGMP modulator (i.e. sildenafil) counteracted while the pretreatment of NO/sGC inhibitor (i.e. methylene blue) potentiated the effect of pyridoxine in TST and FST. Pretreatment of NO donor did not influence, pretreatment of NO/sGC inhibitor decreased while the pretreatment of cGMP modulator increased the level of brain nitrite in pyridoxine treated mice. Further the pretreatment of NO donor and cGMP modulator decreased while the pretreatment of NO/sGC inhibitor increased the level of brain serotonin in pyridoxine treated mice. Pyridoxine thus exerted antidepressant like effect and NO-sGC-cGMP signaling modulated the antidepressant like effect of pyridoxine in mice.

Antidepressant Like Effect of Ascorbic Acid in Mice: Possible Involvement of NO-sGC-cGMP Signaling.

The present study was designed to determine the antidepressant like activity of ascorbic acid (AA) in mice. Further the influence of NO-sGC-cGMP signaling in the antidepressant like effect of AA in mice was determined. Male swiss albino mice were used in the present study. Mice in the control group received saline and fluoxetine (10 mg/kg, i.p.) was used as the standard antidepressant drug. AA (50, 100 and 150 mg/kg, i.p.) was administered to the mice and depression related behavior were determined using tail suspension test (TST) and forced swim test (FST). Further the whole brain nitrite and serotonin levels were also determined. It was observed that the administration of AA (100 mg/kg, i.p.) reversed the depression like behavior in mice in TST and FST. AA (100 mg/kg, i.p.) treatment decreased the level of nitrite and increased the level of serotonin in the brain of mice significantly as compared to control. Further the behavioral and neurochemical effect of AA (50 mg/kg, i.p) was studied in NO modulator [NO donor: L-Arginine (50 mg/kg, i.p); NO-sGC inhibitor: methylene blue (1 mg/kg, i.p.) and cGMP modulator: sildenafil (1 mg/kg, i.p.)] pretreated mice. It was observed that the pretreatment of NO donor and cGMP modulator counteracted the effect conferred by AA (50 mg/kg, i.p). While the pretreatment of NO-sGC inhibitor potentiated the effect conferred by AA (50 mg/kg, i.p). The present study suggested that the AA confer antidepressant like effect in mice and NO-sGC-cGMP signaling pathway influence the antidepressant like effect of AA in mice.

Therapeutic potential of mangiferin in the treatment of various neuropsychiatric and neurodegenerative disorders.

Xanthones are important chemical class of bioactive products that confers therapeutic benefits. Of several xanthones, mangiferin is known to be distributed widely across several fruits, vegetables and medicinal plants. Mangiferin has been shown to exert neuroprotective effects in both in-vitro and in-vivo models. Mangiferin attenuates cerebral infarction, cerebral edema, lipid peroxidation (MDA), neuronal damage, etc. Mangiferin further potentiate levels of endogenous antioxidants to confer protection against the oxidative stress inside the neurons. Mangiferin is involved in the regulation of various signaling pathways that influences the production and levels of proinflammatory cytokines in brain. Mangiferin cosunteracted the neurotoxic effect of amyloid-beta, MPTP, rotenone, 6-OHDA etc and confer protection to neurons. These evidence suggested that the mangiferin may be a potential therapeutic strategy for the treatment of various neurological disorders. The present review demonstrated the pharmacodynamics-pharmacokinetics of mangiferin and neurotherapeutic potential in several neurological disorders with underlying mechanisms.

Anxiolytic like effect of L-Carnitine in mice: Evidences for the involvement of NO-sGC-cGMP signaling pathway.

L-Carnitine (LC) is an endogenous compound synthesized from the essential amino acids lysine and methionine. LC act as an antioxidant and modulates the levels of neurochemicals such as glutamate, GABA, NO etc. implicated in the regulation of anxiety and related behavior. However its exact role in the anxiety is not known. The present study was designed to investigate the anxiolytic like effect of LC in mice. LC (2.5, 5.0 and 10 mg/kg, i.p.) was administered to the mice and the anxiety related behavior was determined using light and dark box (LDB) and elevated plus maze (EPM) tests. The whole brain nitrite level was also determined. The results obtained demonstrated that LC (10 mg/kg, i.p.) exerted anxiolytic like effect in mice, accompanied by the reduction of whole brain nitrite level significantly as compared to control. Further, the influence of NO and GABA modulators pretreatments on the effect of subtherapeutic dose of LC was also determined. The results obtained demonstrated that NO donor/cGMP modulator counteracted while NO inhibitor potentiated the effect confers by the subtherapeutic dose of LC mice. Pretreatment of diazepam (1 mg/kg, i.p.) further potentiated the effect of subtherapeutic dose of LC (5 mg/kg, i.p.) in EPM and LDB tests and further reduced the brain nitrite level significantly as compared to LC (5 mg/kg, i.p.) alone treatment. Thus, LC exerted anxiolytic like effect in mice and NO-sGC-cGMP signaling pathway influences the anxiolytic like effect of LC in mice.

Amantadine exerts anxiolytic like effect in mice: Evidences for the involvement of nitrergic and GABAergic signaling pathways.

Amantadine is a glutamatergic antagonist that works by inhibiting the NMDA receptor. Besides the inhibition of NMDA receptors amantadine also stabilizes the glutamatergic system and protects the neurons against the NMDA toxicity. Amantadine treatment also reduces the production of NO and metabolism of GABA. Therefore amantadine modulates glutamate, GABA and NO which are known to be implicated in the pathogenesis of anxiety and related behavior. The present study was designed to investigate the anxiolytic like effect of amantadine in mice. Nitrergic and GABAergic signaling influence in the anxiolytic like effect of amantadine was also studied. Amantadine (25, 50 and 75 mg/kg, i.p.) was administered and the anxiety related behavior was determined using light and dark box (LDB) and elevated plus maze (EPM) methods. Further, the effect of various treatments on the whole brain glutamate, nitrite and GABA levels were also determined. The results obtained demonstrated that the amantadine (50 mg/kg, i.p.) exerted anxiolytic like effect in mice and reduced the levels of glutamate, nitrite and GABA in the brain of mice as compared to control. Further, the influence of NO and GABA in the anxiolytic like effect of the amantadine was also determined. The results obtained demonstrated that NO donor counteracted while NO inhibitor potentiated the anxiolytic like effect of amantadine in mice. Also the combined treatment of amantadine (25 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) did not affect the anxiety related behavior, brain GABA and nitrite level of mice but reduced the levels the brain glutamate levels significantly as compared to amantadine (25 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) treated mice. Thus, amantadine exerted anxiolytic like effect in mice and the anxiolytic like effect of amantadine was modulated by nitrergic and GABAergic signaling pathway.

Lithium potentiated, pyridoxine abolished and fluoxetine attenuated the anxiolytic effect of diazepam in mice.

In the present study, the anxiolytic effect of diazepam (1 and 2 mg/kg, i.p.) was determined alone and in combination with lithium (50 mg/kg, i.p.), pyridoxine (90 mg/kg, i.p.) and fluoxetine (10 mg/kg, i.p.) using elevated plus maze (EPM) and light/dark box (LDB) tests in experimental mice. The effect of various treatments on the brain GABA levels and glutamic acid decarboxylase (GAD) expression were also determined. The results obtained suggested that the diazepam (2 mg/kg, i.p.) exerted anxiolytic effect and significantly increased the brain GABA levels and GAD expression as compared to control group. Fluoxetine (10 mg/kg, i.p.) exerted anxiogenic effects, but did not affect the brain GABA levels and GAD activity significantly as compared to control. Pretreatments of pyridoxine (90 mg/kg, i.p.) abolished; lithium (50 mg/kg, i.p.) potentiated while fluoxetine (10 mg/kg, i.p.) attenuated the anxiolytic and neurochemical effects of diazepam (1 and 2 mg/kg, i.p.) treatment in mice. Therefore, the combined treatment of lithium and diazepam might be a promising treatment for anxiety.

Nitrergic signaling modulation by ascorbic acid treatment is responsible for anxiolysis in mouse model of anxiety.

The present study was designed to investigate the effect of ascorbic acid (AA) treatment on the anxiety related behavioral and neurochemical alterations. AA (50, 100 and 200 mg/kg, i.p.) was administered to the mice and anxiety related behavior and levels of glutamate and nitrite in the brain of mice were determined. The results obtained revealed that the administration of AA (100 mg/kg, i.p.) significantly reduced the anxiety related behavior and the levels of nitrite in the brain of mice. Nitrergic interactions were further determined by the pretreatment of mice with nitric oxide (NO) modulator and AA treatment followed by behavioral and neurochemical measurements. The results obtained suggested that NO inhibition potentiated the anxiolytic like activity of AA in mice. It was also observed that the glutamate and nitrite level in the brain of mice were significantly reduced by the NO inhibitor pretreatment. Thus, the present study demonstrated the possible nitrergic pathways modulation in the anxiolytic like activity of AA in mice.

NO-sGC-cGMP signaling influence the anxiolytic like effect of lithium in mice in light and dark box and elevated plus maze.

Glutamate is an excitatory neurotransmitter implicated in the pathogenesis of psychiatric disorders. Glutamate results in the activation of an enzyme called glycogen synthase kinase-3 (GSK-3) acting through N-methyl-d-aspartate (NMDA) receptors. Impaired expression of GSK-3 affects behavior and neurochemicals level in the brain responsible for the pathogenesis of mood disorders. It has been reported that lithium acts as an inhibitor of GSK-3 and inhibit the enzyme GSK-3 in an uncompetitive manner. In the present study, anxiolytic like effect of lithium in mice is investigated through light and dark box (LDB) and elevated plus maze (EPM). Lithium (50, 100 and 200 mg/kg, i.p.) was administered to the mice to determine the anxiety related behavior. Results obtained suggests that the administration of lithium (100 mg/kg, i.p.) reversed the anxiety related behavior of mice and decreased the levels of glutamate and nitrite as compared to control. Glutamate acting through the NMDA receptor has been found to regulate the expression of enzyme neuronal nitric oxide synthase (nNOS), which is responsible for the release of nitric oxide (NO), suggesting a possible link between NO and GSK-3 also. Therefore, to determine the possible interaction with NO, sub-effective dose of lithium was administered in combination with NO donor i.e. l-Arginine (50 mg/kg, i.p.), NOS and soluble guanylate cyclase (sGC) inhibitor i.e. methylene blue (1 mg/kg, i.p.) and phosphodiesterase inhibitor i.e. sildenafil (1 mg/kg, i.p.). The results obtained demonstrated that the anxiolytic like effect of lithium was abolished by the pretreatment with NO donor and potentiated by the pretreatment with NOS inhibitor. Therefore, it is suggested that NO signaling pathway influence the anxiolytic like activity of lithium in mice, further suggesting the link between the GSK-3 and NO signaling in the regulation of anxiety related behavior.

Anxiolytic-like effect of pyridoxine in mice by elevated plus maze and light and dark box: Evidence for the involvement of GABAergic and NO-sGC-cGMP pathway.

Present study was carried out to investigate the 'anxiolytic-like' effect of pyridoxine in mice. Pyridoxine (90, 180 and 360 mg/kg) was administered by intraperitoneal (i.p.) route to the experimental mice and anxiety-related behavior was evaluated by light and dark box (LDB) and elevated plus maze (EPM) models. Glutamate, GABA and nitrite levels were also determined in the isolated whole brain of mice. It was observed that pyridoxine (180 mg/kg, i.p.) exerted 'anxiolytic-like' effect in mice in EPM and LDB models. Also, there was a significant increase in the levels of GABA whereas; the levels of glutamate and nitrite were decreased as compared to the control group. Administration of pentamethylene tetrazole (PTZ; 20 mg/kg, i.p.) exerted anxiogenic effects in mice, but the combination of PTZ and pyridoxine (180 mg/kg, i.p.) abolished the 'anxiolytic-like' effect of pyridoxine, thereby, suggesting the possible role of GABA in the 'anxiolytic-like' effect of pyridoxine in mice. Further, the influence of NO-sGC-cGMP pathway was investigated by administering the sub-effective dose of pyridoxine in combination with sub-threshold doses of NO modulators i.e. l­arginine (50 mg/kg, i.p.; NO donor); methylene blue (1 mg/kg, i.p.; NO and soluble guanylate cyclase inhibitor) and sildenafil (1 mg/kg, i.p.; phosphodiesterase inhibitor and cGMP modulator). It was observed that the 'anxiolytic-like' effect of pyridoxine in mice was counteracted by the NO donor and potentiated by the NO inhibitors. Thus, the present study confirmed the involvement of GABAergic and NO-sGC-cGMP pathway in the 'anxiolytic-like' effect of pyridoxine in mice.