Agmatine alleviates ethanol withdrawal-associated cognitive impairment and neurochemical imbalance in rats.

The present study aimed to investigate the role of agmatine in the neurobiology underlying memory impairment during ethanol withdrawal in rats. Sprague-Dawley rats were subjected to a 21-day chronic ethanol exposure regimen (2.4 % w/v ethanol for 3 days, 4.8 % w/v for the next 4 days, and 7.2 % w/v for the following 14 days), followed by a withdrawal period. Memory impairment was assessed using the passive avoidance test (PAT) at 24, 48, and 72 h post-withdrawal. The ethanol-withdrawn rats displayed a significant decrease in step-through latency in the PAT, indicative of memory impairment at 72 h post-withdrawal. However, administration of agmatine (40 µg/rat) and its modulators (L-arginine, arcaine, and amino-guanidine) significantly increases the latency time in the ethanol-withdrawn rats, demonstrating the attenuation of memory impairment. Further, pretreatment with imidazoline receptor agonists enhances agmatine's effects, while antagonists block them, implicating imidazoline receptors in agmatine's actions. Neurochemical analysis in ethanol-withdrawn rats reveals dysregulated glutamate and GABA levels, which was attenuated by agmatine and its modulators. By examining the effects of agmatine administration and modulators of endogenous agmatine, the study aimed to shed light on the potential therapeutic implications of agmatinergic signaling in alcohol addiction and related cognitive deficits. Thus, the present findings suggest that agmatine administration and modulation of endogenous agmatine levels hold potential as therapeutic strategies for managing alcohol addiction and associated cognitive deficits. Understanding the neurobiology underlying these effects paves the way for the development of novel interventions targeting agmatinergic signaling in addiction treatment.

Agmatine as a novel intervention for Alzheimer's disease: Pathological insights and cognitive benefits.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive cognitive decline and a significant societal burden. Despite extensive research and efforts of the multidisciplinary scientific community, to date, there is no cure for this debilitating disease. Moreover, the existing pharmacotherapy for AD only provides symptomatic support and does not modify the course of the illness or halt the disease progression. This is a significant limitation as the underlying pathology of the disease continues to progress leading to the deterioration of cognitive functions over time. In this milieu, there is a growing need for the development of new and more efficacious treatments for AD. Agmatine, a naturally occurring molecule derived from L-arginine, has emerged as a potential therapeutic agent for AD. Besides this, agmatine has been shown to modulate amyloid beta (Aß) production, aggregation, and clearance, key processes implicated in AD pathogenesis. It also exerts neuroprotective effects, modulates neurotransmitter systems, enhances synaptic plasticity, and stimulates neurogenesis. Furthermore, preclinical and clinical studies have provided evidence supporting the cognition-enhancing effects of agmatine in AD. Therefore, this review article explores the promising role of agmatine in AD pathology and cognitive function. However, several limitations and challenges exist, including the need for large-scale clinical trials, optimal dosing, and treatment duration. Future research should focus on mechanistic investigations, biomarker studies, and personalized medicine approaches to fully understand and optimize the therapeutic potential of agmatine. Augmenting the use of agmatine may offer a novel approach to address the unmet medical need in AD and provide cognitive enhancement and disease modification for individuals affected by this disease.

Revisiting the Mitochondrial Function and Communication in Neurodegenerative Diseases.

Neurodegenerative disorders are distinguished by the progressive loss of anatomically or physiologically relevant neural systems. Atypical mitochondrial morphology and metabolic malfunction are found in many neurodegenerative disorders. Alteration in mitochondrial function can occur as a result of aberrant mitochondrial DNA, altered nuclear enzymes that interact with mitochondria actively or passively, or due to unexplained reasons. Mitochondria are intimately linked to the Endoplasmic reticulum (ER), and ER-mitochondrial communication governs several of the physiological functions and procedures that are disrupted in neurodegenerative disorders. Numerous researchers have associated these disorders with ER-mitochondrial interaction disturbance. In addition, aberrant mitochondrial DNA mutation and increased ROS production resulting in ionic imbalance and leading to functional and structural alterations in the brain as well as cellular damage may have an essential role in disease progression via mitochondrial malfunction. In this review, we explored the evidence highlighting the role of mitochondrial alterations in neurodegenerative pathways in most serious ailments, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD).

Recent Perspectives on Cardiovascular Toxicity Associated with Colorectal Cancer Drug Therapy.

Cardiotoxicity is a well-known adverse effect of cancer-related therapy that has a significant influence on patient outcomes and quality of life. The use of antineoplastic drugs to treat colorectal cancers (CRCs) is associated with a number of undesirable side effects including cardiac complications. For both sexes, CRC ranks second and accounts for four out of every ten cancer deaths. According to the reports, almost 39% of patients with colorectal cancer who underwent first-line chemotherapy suffered cardiovascular impairment. Although 5-fluorouracil is still the backbone of chemotherapy regimen for colorectal, gastric, and breast cancers, cardiotoxicity caused by 5-fluorouracil might affect anywhere from 1.5% to 18% of patients. The precise mechanisms underlying cardiotoxicity associated with CRC treatment are complex and may involve the modulation of various signaling pathways crucial for maintaining cardiac health including TKI ErbB2 or NRG-1, VEGF, PDGF, BRAF/Ras/Raf/MEK/ERK, and the PI3/ERK/AMPK/mTOR pathway, resulting in oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis, ultimately damaging cardiac tissue. Thus, the identification and management of cardiotoxicity associated with CRC drug therapy while minimizing the negative impact have become increasingly important. The purpose of this review is to catalog the potential cardiotoxicities caused by anticancer drugs and targeted therapy used to treat colorectal cancer as well as strategies focused on early diagnosing, prevention, and treatment of cardiotoxicity associated with anticancer drugs used in CRC therapy.

Overview on the Polyphenol Avenanthramide in Oats (Avena sativa Linn.) as Regulators of PI3K Signaling in the Management of Neurodegenerative Diseases.

Avenanthramides (Avns) and their derivatives, a group of polyphenolic compounds found abundantly in oats (Avena sativa Linn.), have emerged as promising candidates for neuroprotection due to their immense antioxidant, anti-inflammatory, and anti-apoptotic properties. Neurodegenerative diseases (NDDs), characterized by the progressive degeneration of neurons, present a significant global health burden with limited therapeutic options. The phosphoinositide 3-kinase (PI3K) signaling pathway plays a crucial role in cell survival, growth, and metabolism, making it an attractive target for therapeutic intervention. The dysregulation of PI3K signaling has been implicated in the pathogenesis of various NDDs including Alzheimer's and Parkinson's disease. Avns have been shown to modulate PI3K/AKT signaling, leading to increased neuronal survival, reduced oxidative stress, and improved cognitive function. This review explores the potential of Avn polyphenols as modulators of the PI3K signaling pathway, focusing on their beneficial effects against NDDs. Further, we outline the need for clinical exploration to elucidate the specific mechanisms of Avn action on the PI3K/AKT pathway and its potential interactions with other signaling cascades involved in neurodegeneration. Based on the available literature, using relevant keywords from Google Scholar, PubMed, Scopus, Science Direct, and Web of Science, our review emphasizes the potential of using Avns as a therapeutic strategy for NDDs and warrants further investigation and clinical exploration.

Molecular understanding of ER-MT communication dysfunction during neurodegeneration.

Biological researchers are seeing organelles in a new light. These cellular entities have been believed to be singular and distinctive structures that performed specialized purposes for a very long time. But in recentpast years, scientists have learned that organelles become dynamic and make physical contact. Additionally, Biological processes are regulated by organelles interactions and its alteration play an important role in cell malfunctioning and several pathologies, including neurodegenerative diseases. Mitochondrial-ER contact sites (MERCS) have received considerable attention in the domain of cell homeostasis and dysfunction, specifically in the area of neurodegeneration. This is largely due to the significant role of this subcellular compartment in a diverse array of vital cellular functions, including Ca2+ homeostasis, transport, bioenergetics and turnover, mitochondrial dynamics, apoptotic signaling, ER stress, and inflammation. A significant number of disease-associated proteins were found to physically interact with the ER-Mitochondria (ER-MT) interface, causing structural and/or functional alterations in this compartment. In this review, we summarize current knowledge about the structure and functions of the ER-MT contact sites, as well as the possible repercussions of their alteration in notable neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and fronto-temporal dementia. The constraints and complexities in defining the nature and origin of the highlighted defects in ER-MT communication, as well as their concise contribution to the neurodegenerative process, are illustrated in particular. The possibility of using MERCS as a potential drug target to prevent neuronal damage and ultimately neurodegeneration is the topic of our final discussion.

Mitochondrial Dysfunction as a Signaling Target for Therapeutic Intervention in Major Neurodegenerative Disease.

Neurodegenerative diseases (NDD) are incurable and the most prevalent cognitive and motor disorders of elderly. Mitochondria are essential for a wide range of cellular processes playing a pivotal role in a number of cellular functions like metabolism, intracellular signaling, apoptosis, and immunity. A plethora of evidence indicates the central role of mitochondrial functions in pathogenesis of many aging related NDD. Considering how mitochondria function in neurodegenerative diseases, oxidative stress, and mutations in mtDNA both contribute to aging. Many substantial reports suggested the involvement of numerous contributing factors including, mitochondrial dysfunction, oxidative stress, mitophagy, accumulation of somatic mtDNA mutations, compromised mitochondrial dynamics, and transport within axons in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis. Therapies therefore target fundamental mitochondrial processes such as energy metabolism, free-radical generation, mitochondrial biogenesis, mitochondrial redox state, mitochondrial dynamics, mitochondrial protein synthesis, mitochondrial quality control, and metabolism hold great promise to develop pharmacological based therapies in NDD. By emphasizing the most efficient pharmacological strategies to target dysfunction of mitochondria in the treatment of neurodegenerative diseases, this review serves the scientific community engaged in translational medical science by focusing on the establishment of novel, mitochondria-targeted treatment strategies.

Agmatine prevents the manifestation of impulsive burying and depression-like behaviour in progesterone withdrawn female rats.

Premenstrual dysphoric disorder (PMDD) is characterized by various physical and affective symptoms, including anxiety, irritability, anhedonia, social withdrawal, and depression. The present study investigated the role of the agmatinergic system in animal model of progesterone withdrawal in female rats. Chronic progesterone exposure of female rats for 21 days and its abrupt withdrawal showed enhanced marble burying, increased immobility time, and reduced no. of entries in open arm as compared to control animals. The progesterone withdrawal-induced enhanced marble burying anxiety and immobility time was significantly attenuated by agmatine (5-20 mg/kg, i.p.), and its endogenous modulators like L-arginine (100 mg/kg, i.p.), amino-guanidine (25 mg/kg, i.p.) and arcaine (50 mg/kg, i.p.) by their once-daily administration from day 14-day 21 of the protocol. We have also analysed the levels of agmatine, progesterone, and inflammatory cytokines in the hippocampal region of progesterone withdrawn rats. There was a significant decline in agmatine and progesterone levels and an elevation in cytokine levels in the hippocampal region of progesterone withdrawn rats compared to the control animals. In conclusion, the present studies suggest the importance of the endogenous agmatinergic system in progesterone withdrawal-induced anxiety-like and depression-like behaviour. The data also projects agmatine as a potential therapeutic target for the premenstrual dysphoric disorder.

Mitophagy regulation in aging and neurodegenerative disease.

Mitochondria are the primary cellular energy generators, supplying the majority of adenosine triphosphate through oxidative phosphorylation, which is necessary for neuron function and survival. Mitophagy is the metabolic process of eliminating dysfunctional or redundant mitochondria. It is a type of autophagy and it is crucial for maintaining mitochondrial and neuronal health. Impaired mitophagy leads to an accumulation of damaged mitochondria and proteins leading to the dysregulation of mitochondrial quality control processes. Recent research shows the vital role of mitophagy in neurons and the pathogenesis of major neurodegenerative diseases. Mitophagy also plays a major role in the process of aging. This review describes the alterations that are being caused in the mitophagy process at the molecular level in aging and in neurodegenerative diseases, particularly Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis, also looks at how mitophagy can be exploited as a therapeutic target for these diseases.

Folate-Mediated Paclitaxel Nanodelivery Systems: A Comprehensive Review.

Paclitaxel (PTX) is used as a viable cancer medication in the chemotherapy of breast, ovarian, lung, bladder, neck, head, and esophageal tumors. The focus of this review is to survey various folate-targeting PTX-loaded nanopreparations in both research and clinical applications. There are diverse nanopreparations, including liposomes, micelles, polymeric nanopreparations, lipid nanopreparations, lipoprotein nanocarriers, and other inorganic nanopreparations for folate-associated PTX tumor targeting. Here, the folate targeting PTX-loaded nanopreparations, which have promising results in the constructive treatment of cancer by reducing toxic side-effects and/or improving effectiveness, was mainly reviewed.

Chronic agmatine treatment prevents olanzapine-induced obesity and metabolic dysregulation in female rats.

Antipsychotic-induced obesity affects millions of people and is a serious health condition worldwide. Olanzapine is the most widely prescribed antipsychotic agent with high obesogenic potential. However, the exact mechanism by which it causes its metabolic dysregulation remains poorly understood. In this study, we investigated the effect of agmatine in olanzapine-induced metabolic derangements in Female Sprague-Dawley rats. Repeated olanzapine administration for 28 days increased body weight while treatment with agmatine from days 15 to 28 prevented the body weight gain induced by olanzapine without any alteration in food intake. Repeated agmatine treatment decreased the elevated feeding efficiency and adiposity index, as well as improved dysregulated lipid metabolism induced by olanzapine. Increased activity of fatty acid synthase (FAS) and decreased expression of carnitine palmitoyl transferase-1 (CPT-1) were detected in chronic olanzapine-treated rats. Although agmatine treatment did not alter FAS activity, it increased CPT-1 activity. It is possible that the inhibitory effect of agmatine on weight gain and adiposity might be associated with increased mitochondrial fatty acid oxidation and energy expenditure in olanzapine-treated rats. We suggest that agmatine can be explored for the prevention of obesity complications associated with chronic antipsychotic treatment.

Involvement of molecular chaperone in protein-misfolding brain diseases.

Protein misfolding causes aggregation and build-up in a variety of brain diseases. There are numeral molecules that are linked with the protein homeostasis mechanism. Molecular chaperones are one of such molecules that are responsible for protection against protein misfolded and aggregation-induced neurotoxicity. Many studies have explored the participation of molecular chaperones in Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, and Huntington's diseases. In this review, we highlighted the constructive role of molecular chaperones in neurological diseases characterized by protein misfolding and aggregation and their capability to control aberrant protein interactions at an early stage thus successfully suppressing pathogenic cascades. A comprehensive understanding of the protein misfolding associated with brain diseases and the molecular basis of involvement of chaperone against aggregation-induced cellular stress might lead to the progress of new therapeutic intrusion-related to protein misfolding and aggregation.

Alzheimer's disease and sleep disorders: Insights into the possible disease connections and the potential therapeutic targets.

One of the comorbid conditions in an individual with Alzheimer's disease is a sleep disorder. Clinical features of sleep disorders involve various sleep disturbances such as Obstructive Sleep Apnea (OSAS), Excessive Daytime Sleepiness (EDS), Rapid Eye Movement (REM), Breathing Disorders, Periodic limb movements in sleep (PLMS), etc. The primary tools used for the identification of such disturbances are Polysomnography (PSG) and Wrist actigraphy. This review will highlight and explains the different approaches used in the treatment of sleep disorders. Non-pharmacological treatments include Peter Hauri rules, sleep education program, and light therapy which play a key role in the regulation of sleep-wake cycles. Pharmacological therapy described in this article may be useful in treating sleep destruction in patients with Alzheimer's disease. Along with the Non-pharmacological and pharmacological treatment, here we discuss five commonly recognized plant-based nutraceuticals with hypothesized impact on sleep disorders: caffeine, chamomile, cherries, L-tryptophan, and valerian by the proper emphasis on the known mechanism of their action.

Evidences for agmatine alterations in Aß1-42induced memory impairment in mice.

Alzheimer's disease is an age related progressive neurodegenerative disorder characterized by decline in cognitive functions, such as memory loss and behavioural abnormalities. The present study sought to assess alterations in agmatine metabolism in the beta-amyloid (Aß1-42) Alzheimer's disease mouse model. Aß1-42 injected mice showed impairment of cognitive functioning as evidenced by increased working and reference memory errors in radial arm maze (RAM). This cognitive impairment was associated with a reduction in the agmatine levels and elevation in its degrading enzyme, agmatinase, whereas reduced immunocontent was observed in its synthesizing enzyme arginine decarboxylase expression within hippocampus and prefrontal cortex. Chronic agmatine treatment and its endogenous modulation by l-arginine, or arcaine or aminoguanidine prevented the learning and memory impairment induced by single intracranial Aß1-42 peptide injection. In conclusion, the present study suggests the importance of the endogenous agmatinergic system in ß-amyloid induced memory impairment in mice.

Agmatine improves the behavioral and cognitive impairments associated with chronic gestational ethanol exposure in rats.

Chronic maternal ethanol exposure leads to poor intelligence, impaired cognition and array of neurological symptoms in offsprings and commonly referred as fetal alcohol spectrum disorder (FASD). Despite high prevalence and severity, the neurochemical basis of FASD remains largely unexplored. The present study evaluated the pharmacological effects of agmatine in cognitive deficits associated with FAS in rat's offsprings prenatally exposed to alcohol. Pregnant rats received ethanol in liquid modified diet during the entire gestational period of 21 days. Offsprings were treated with agmatine (20-80 mg/Kg, i.p.) during early postnatal days (PND: 21-35) and subsequently evaluated for anxiety in elevated plus maze (EPM), depression in forced swim test (FST) and learning and memory in Morris's water maze (MWM) during post adolescent phase. Hippocampal agmatine, BDNF, TNF-α and IL-6 levels were also analyzed in prenatally ethanol exposed pups. Offsprings prenatally exposed to ethanol demonstrated delayed righting reflex, reduced exploratory behavior along with anxiety, depression-like behavior and impaired memory. These behavioral abnormalities were correlated with a significant reduction in hippocampal agmatine and BDNF levels and elevation in TNF-α and IL-6 immunocontent. Chronic agmatine (40 and 80 mg/Kg, i.p.) administration for 15 days (PND: 21-35), improved entries and time spent in open arm of EPM, decreased immobility time in FST. It also reduced latency to reach the platform location; increased the number of entries, time spent in platform quadrant and also number of crossing over platform quadrant when subjected to MWM test in prenatally ethanol exposed offsprings. This study provides functional evidences for the therapeutic potential of agmatine in cognitive impairment and other neurological complications associated with FASD.

Inhibitory influence of agmatine in ethanol withdrawal-induced depression in rats: Behavioral and neurochemical evidence.

Although ethanol withdrawal depression is one of the prominent reasons for ethanol consumption reinstatement and ethanol dependence, its neurochemical basis is not clearly understood. The present study investigated the role of the agmatinergic system in ethanol withdrawal-induced depression using the forced swim test (FST) in rats. Chronic exposure of animals to ethanol for 21 days and its abrupt withdrawal produced depression-like behavior, as evidenced by increased immobility time in the FST, compared to the pair-fed control animals. The ethanol withdrawal-induced depression was significantly attenuated by agmatine (20-40 µg/rat, i.c.v. [intracerebroventricularly]), moxonidine (50 µg/rat, i.c.v.), 2-BFI (20 µg/rat, i.c.v.), L-arginine (80 µg/rat, i.c.v.), amino-guanidine (25 µg/rat, i.c.v.), and arcaine (50 µg/rat, i.c.v.) by their once-daily administration during the withdrawal phase (Days 21, 22, and 23). The antidepressant effect of agmatine in ethanol-withdrawn rats was potentiated by the imidazoline receptor I1 agonist moxonidine (25 µg/rat, i.c.v.) and the imidazoline receptor I2 agonist, 2-BFI (10 µg/rat, i.c.v.) at their sub-effective doses. On the other hand, it was completely blocked by the imidazoline receptor I1 antagonist, efaroxan (10 µg/rat, i.c.v.) and the imidazoline receptor I2 antagonist, idazoxan (4 µg/rat, i.c.v.). In addition, agmatine levels were significantly reduced in brain samples of ethanol-withdrawn rats as compared to the pair-fed control animals. In conclusion, the present study suggests the importance of the endogenous agmatinergic system and the imidazoline receptors system in ethanol withdrawal-induced depression. The data project agmatine as a potential therapeutic target for the alcohol withdrawal-induced depression.

Agmatine reverses ethanol consumption in rats: Evidences for an interaction with imidazoline receptors.

Alcohol is one of the most widely abused recreational drugs, largely linked with serious health and social concerns. However, the treatment options for alcohol-use disorders have limited efficacy and exhibit a range of adverse drug reactions. Large numbers of preclinical studies have projected a biogenic amine, agmatine as a promising potential treatment option for drug addiction, including alcoholism. In the present study, administration of agmatine (20-40 mg/kg, i.p.) resulted in significant inhibition of ethanol self-administration in the right p-VTA in operant conditioning paradigm. Further, acute intracranial administration of agmatine (20 and 40 µg/rat) significantly reduced the ethanol consumption in the two bottle choice paradigm. Agmatine is degraded to putrescine and guanido-butanoic acid by the enzyme agmatinase and diamine oxidase respectively and inhibition of these enzymes results in augmentation of endogenous agmatine. In the present study, diamine oxidase inhibitor, aminoguanidine and agmatinase inhibitor, arcaine were used to block the agmatine metabolic pathways to increase brain agmatine levels. Drugs that augment endogenous agmatine levels like L-arginine (80 µg/rat, i.c.v.) or arcaine (50 µg/rat, i.c.v.) and aminoguanidine (25 µg/rat, i.c.v.) also reduced the ethanol consumption following their central administration. The pharmacological effect of agmatine on ethanol consumption was potentiated by imidazoline receptor agonists, I1 agonist moxonidine (25 µg/rat, i.c.v.), and imidazoline I2 agonist, 2-BFI (10 µg/rat, i.c.v.) and was blocked by imidazoline I1 antagonist, efaroxan (10 µg/rat, i.c.v.), and I2 antagonist, idazoxan (4 µg/rat, i.c.v.) at their ineffective doses per se. Thus, our result suggests the involvement of imidazoline I1 and I2 receptors in agmatine induced inhibition of ethanol consumption in rats.

Enhanced transdermal permeation and anti-inflammatory potential of phospholipids complex-loaded matrix film of umbelliferone: Formulation development, physico-chemical and functional characterization.

In the present study, umbelliferone - phospholipids complex - loaded matrix film (UPLC - MF) was developed with a goal of improving transdermal permeation and anti-inflammatory potential of umbelliferone (UMB). Umbelliferone - phospholipids complex (UPLC) was prepared using solvent evaporation method. UPLC-MF was prepared by simple and reproducible solvent casting method. Prepared UPLC and UPLC-MF were both physico-chemically characterized by Fourier transforms infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), powder x-ray diffraction (PXRD), proton nuclear magnetic resonance spectroscopy (1H NMR), weight variation, thickness, tensile strength, folding endurance, % elongation, moisture content and uptake Functional characterization of UPLC and UPLC-MF was carried out by solubility analysis, in vitro dissolution, diffusion, and ex vivo permeation via dialysis and biological membrane. UPLC - MF was also evaluated for in vivo anti-inflammatory activity using carrageenan-induced Albino rat paw model. Design-based optimal values for formulation and process variables of UPLC were observed to be 1:1.78, 50 °C and 2 h, respectively. Physico-chemical characterization confirmed the formation of the complex and the film. UPLC demonstrated a higher aqueous solubility (~11-fold), compared to pure UMB. Rate and extent of dissolution of UMB from UPLC was enhanced significantly to that of pure UMB. Compared to UMB-MF, the diffusion and permeation rate of UMB from UPLC-MF enhanced significantly. The UPLC - MF improved the anti-inflammatory potential of UMB by significant enhancement of edema inhibition (%), compared to UMB-MF. The obtained results showed that the present combined formulation system could be employed as a promising strategy for improving transdermal permeation of UMB.

Development of self-assembled nanocarriers to enhance antitumor efficacy of docetaxel trihydrate in MDA-MB-231 cell line.

Self-assembled nanocarriers (SANs) as a novel colloidal controlled delivery for docetaxel trihydrate (DTX) were engineered by high-pressure homogenization method to overcome the several clinical problems. Drug-excipient compatibility was studied using DSC and FTIR spectroscopy. The fabricated SANs was characterized by particle size, zeta potential, and SEM. QbD based central composite design of experiment was employed for formula optimization. The cell viability of DTX-hydroalcoholic solution (DTX-HA) and DTX-loaded SANs has been determined in MDA-MB-231 cell line by MTT assay. The stability study of selected SANs formulations were carried out at various storage conditions as per ICH guidelines. The summary of results obtained shows high drug content with higher entrapment efficiency (91.23 ±â€¯3.41% w/w) of DTX-loaded SANs. It shows diffusion controlled release of DTX over the period of 12 h which is higher than DTX-HA solution, releases the DTX within 4 h. The MTT assay expressed lower cellular viability and improved cell inhibition leads to increase cytotoxicity of formulations towards cells. The stability study reveals stability of DTX-loaded SANs formulations at various storage conditions over a period of three months. The strong experimental evidence confirms the SANs as an effective approach to formulate the controlled delivery system of antineoplastics with improved stability.

Agmatine inhibits nicotine withdrawal induced cognitive deficits in inhibitory avoidance task in rats: Contribution of α2-adrenoceptors.

Nicotine abstinence following chronic exposure is associated with impairments in memory and variety of cognitive functions. Daily nicotine (2 mg/kg, sc, four times daily) administration for 14 days and its abrupt withdrawal significantly impaired avoidance learning in inhibitory avoidance task as indicated by a significant decrease in the step through latency. Animals injected with agmatine (10-40 µg/rat, icv) from day 7 to 14 before the first daily dose of nicotine (2 mg/kg, sc) showed increased step through latencies during retrieval test. Similarly Intracerebroventricular injection of l-arginine (25-100 µg/rat), a biosynthetic precursor of agmatine and arcaine (50 µg -100 µg/rat), an agmatinase inhibitor, also increased the step through latency during retrieval test in nicotine withdrawn animals. In separate experiments, α2-adrenoceptor agonist, clonidine (0.5-1 µg/rat, icv) not only demonstrated significant increase in the step through latency as in nicotine withdrawn rats but also potentiated the pharmacological effect of agmatine. In contrast, pre-treatment of α2-adrenoceptor antagonist, yohimbine (0.5 µg/rat, icv) antagonized the memory enhancing effect of agmatine (20 µg/rat, icv) in nicotine withdrawn rats. In addition, brain agmatine analysis carried out at 72 h time point of nicotine withdrawal showed marked decrease in basal brain agmatine content as compared to control. Overall, the data indicate that agmatine attenuates nicotine withdrawal induced memory impairment through modulation of α2adrenergic receptors. Thus, agmatine might have therapeutic implications in the treatment of cognitive deficits following nicotine withdrawal.