An Update on Autophagy as a Target in the Treatment of Alzheimer's Disease.

Proteostasis is crucial for the maintenance and proper operation of cells. Under typical circumstances, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway are used to clean out undesired, damaged, misfolded, or aggregated proteins. Any dysregulation in the above-mentioned pathways leads to neurodegeneration. One of the most renowned neurodegenerative disorders is AD. This condition is more prevalent in senior people and is frequently linked to dementia, progressive memory loss, and cognitive function decline, which further contributes to cholinergic neuron degradation and synaptic plasticity loss. Extracellular accumulation of amyloid beta plaques and the intraneuronal deposition of misfolded neurofibrillary tangles are two prime pathological reasons for AD. At present, there is no treatment for AD. All that remains available is the symptomatic treatment of this disease. Autophagy is the major mechanism by which the cells degrade the protein aggregates. Deposited immature autophagic vacuoles (AVs) in AD brains suggest interruption of a person's normal autophagy process. This review has briefly covered various forms and mechanisms of autophagy. Furthermore, the discussion in the article is supported by different ways and mechanisms via which autophagy can be stimulated in a beneficial way and can emerge as a novel target in the treatment of various metabolic CNS related disorders. In the current review article, the mTOR-dependent ones are PI3K/Akt/TSC/mTOR, AMPK/TSC/mTOR, and Rag/mTOR pathways and mTOR-independent ones which include Ca2+/calpain, inositol-dependent, cAMP/EPAC/PLC, and JNK1/Beclin-1/PI3K pathways have been discussed in details. The article sheds light on drugs which are validated with details in tabular form from recent updates in clinical trials.

Plants with potential anti-ulcerogenic activity and possible mechanism of actions based on their phyto-constitutional profile.

Gastric ulcer, the most common disorder of the digestive tract is formed due to an imbalance between acid and mucus content of the stomach. However, the currently used western therapeutic regimens have many drawbacks like adverse effects, recurrence of gastric ulcers, are expensive, and also, may have interactions with other drugs. Hence, there is a need for effective alternative therapy. Medicinal herbs have been used since ancient times to treat several diseases and are also evidenced to be effective against gastric ulcers. It is also evident that medicinal herbs have been proved to be equally effective or superior as compared to the existing synthetic medicines. In this review, five herbs have been taken into consideration and assumed to be effective against gastric ulcers. Abrus mollis, Korean Thistle (Cirsium japonicum var. maackii), Astralagus complanatus Bunge, Bauhinia monandra, and Embelia ribes Burm f. are the herbs whose data is been collected and reviewed for their potential gastro-protective action. Although, their side effects and toxicity profile need to be further evaluated. Hence, the purpose of this review is to gather evidence of these five medicinal herbs and their probable mechanism of action against gastric ulcers based on their phyto-constitutional profile.

The roles of HDAC with IMPDH and mTOR with JAK as future targets in the treatment of rheumatoid arthritis with combination therapy.

Various studies have shown that cytokines are important regulators in rheumatoid arthritis (RA). In synovial inflammation alteration of the enzyme HDAC, IMPDH enzyme, mTOR pathway, and JAK pathway increase cytokine level. These increased cytokine levels are responsible for the inflammation in RA. Inflammation is a physiological and normal reaction of the immune system against dangerous stimuli such as injury and infection. The cytokine-based approach improves the treatment of RA. To reach this goal, various researchers and scientists are working more aggressively by using a combination approach. The present review of combination therapy provides essential evidence about the possible synergistic effect of combinatorial agents. We have focused on the effects of HDAC inhibitor with IMPDH inhibitor and mTOR inhibitor with JAK inhibitor in combination for the treatment of RA. Combining various targeted strategies can be helpful for the treatment of RA.

Combinatory Approaches Targeting Cognitive Impairments and Memory Enhancement: A Review.

The objective of this paper is to look at how natural medicines can improve cognition and memory when used with sildenafil, a popular erectile dysfunction medicine that also has nootropic properties. Newer treatment strategies to treat the early stages of these diseases need to be developed. Multiple factors lead to complex pathophysiological conditions, which are responsible for various long-term complications. In this review, a combination of treatments targeting these pathologies is discussed. These combinations may help manage early and later phases of cognitive impairments. The purpose of this article is to discuss a link between these pathologies and a combinational approach with the objective of considering newer therapeutic strategies in the treatment of cognitive impairments. The natural drugs and their ingredients play a major role in the management of disease progression. Additionally, their combination with sildenafil allows for more efficacy and better response. Studies showing the effectiveness of natural drugs and sildenafil are mentioned, and how these combinations could be beneficial for the treatment of cognitive impairments and amnesia are summarised. Furthermore, preclinical and clinical trials are required to explore the medicinal potential of these drug combinations.

Combinational Approaches Targeting Various Aspects Involved in Intestinal Barrier Dysfunction-Induced Anxiety.

Anxiety disorder is one of the most prevalent psychiatric disorders. The high prevalence of comorbid gastrointestinal disorders and anxiety, as well as various limitations in current therapy, have necessitated the search for alternative techniques. The Gut-Brain Axis is the connecting link between the gut and the brain. One of the reasons for the Gut-Brain Axis malfunction resulting in HPA axis stimulation and anxiety is intestinal barrier dysfunction. Gut microorganisms, lipopolysaccharides, and other factors can stimulate the disruption of this intestinal barrier. Tight junction proteins, the epithelial barrier, the mucosal membrane, the Toll-like receptor/Myeloid differentiation factor 88 pathway, the activated immune system, and the HPA axis could all be potential targets for anxiety caused by intestinal barrier disruption. Quercetin and Rebamipide, Berberine and Agomelatine, Angiotensin II receptor type 1 blockers, and Lubiprostone can act on these targets to provide an anxiolytic effect.

Importance of Exploring N-Methyl-D-Aspartate (NMDA) as a Future Perspective Target in Depression.

Major depressive disorder (MDD) is a serious and complex mental illness. Currently, many antidepressants are available in the market for the treatment of MDD. However, these agents are associated with side effects, which restricts their use. This warrants the development of advanced antidepressive medications with a novel mechanism of action or novel targets and with minimal adverse effects. The traditional neurobiological hypothesis of depression, the monoamine hypothesis, is unable to properly explain all the aspects of depressive conditions. In this review, we discuss novel approaches that could be used for the treatment of depression, including glutamatergic and serotonergic system modulation. The pathogenesis of depression is greatly affected by glutamatergic neurotransmission dysfunction. Previous investigations have shown that ketamine, an N-methyl-D-aspartate receptor antagonist, exerts fast and long-lasting antidepressant effects. Several glutamatergic modulators, such as esketamine, sarcosine, and others, have also shown potential antidepressant action in animal as well as clinical studies. Lastly, drugs that alter neurotransmission by NMDA receptors could open up new avenues for more effective treatment of depression. Besides, understanding the underlying mechanisms will aid in the development of novel and fast-acting antidepressant drugs in the future.

Copper-lowering agents as an adjuvant in chemotherapy.

Copper is an important element essential for metabolism and normal human body function. Although it is an essential element, related imbalance leads to toxic effects. Studies have proved that there is an increase in copper level in cancer cells. Evidences suggest the link between increase in copper levels and progression of various types of cancers. Different strategies have been utilized to decrease the level of copper in various types of cancer cells. However, it was observed that cell machinery involved in copper homeostasis plays critical factor in lowering copper levels in cancer cells. The outcomes of many monotherapies consisting copper-lowering agents for the treatment of different types of cancers showed that the inhibition of single factor is not sufficient to inhibit the growth of cancer cells. The combination of copper-lowering agent with chemotherapeutic agent showed synergistic effect. Interestingly, the presence of copper-lowering agent in such combinations significantly improved the efficacy of chemotherapeutic agent. The present work has focused on the discussion of outcomes of studies involving anti-copper agent and chemotherapeutic agent and related future strategies.

Combinational Approaches Targeting Neurodegeneration, Oxidative Stress, and Inflammation in the Treatment of Diabetic Retinopathy.

Diabetic Retinopathy (DR) is one of the most severe ocular problems of diabetes. It is a microvascular complication that impairs the vision of diabetic individuals and can cause acquired blindness. Currently, available treatment options like laser therapy, vitrectomy, intravitreal anti-vascular endothelial growth factor (VEGF) agents, and glucocorticoids help to reduce vision loss at advanced stages. In spite of the available therapies, patients with severe vision loss face difficulty in achieving the normal vision. There is a need for the development of newer treatment strategies to address the condition from the early stages. Multiple factors owing to complex pathophysiological events are responsible for this long-term complication. Neurodegeneration, inflammation, and oxidative stress are the three important factors associated with the development of DR. Oxidative stress is a major contributor to the onset and progression of DR. Pathological events like retinal neurodegeneration and inflammation damage the retina in the early stages of DR. Different combinations of treatments targeting these pathological events are discussed in the present review. The first combination discussed is citicoline and resveratrol and the second combination is duloxetine and N-acetyl cysteine (NAC). These combinations may help in the early stages of DR. CD5-2, and angiopoietin-2 inhibitors is the third combination and this combination may help to manage diabetic macular edema. The main purpose of this article is to discuss the link between these pathologies and the three combinational approaches with the objective of considerating newer therapeutic approaches in research related to DR treatment.

Mini review-vanadium-induced neurotoxicity and possible targets.

Vanadium, a transition metal, ubiquitous in nature is known to have therapeutic effect as well as toxic effect. It is known to possess antidiabetic, antitumor and antiparasitic activity. However, on long term exposure, it produces neurotoxicity which may result in memory impairment. The possible mechanism known to cause neurotoxicity suggested is oxidative stress and inflammation of neuronal cells. The present review has focused on discussing the role of protein P38 mitogen-activated protein kinase and oxidative stress as possible targets to treat vanadium-induced neurotoxicity.

The effect of bupropion augmentation of minocycline in the treatment of depression.

The aim of the current study was to analyse the augmentation of minocycline with bupropion in treating depression. 'Saline' (10 ml/kg), 'minocycline per se' (25 mg/kg), 'minocycline per se' (50 mg/kg), 'bupropion per se' (5 mg/kg), 'bupropion per se' (10 mg/kg) and 'bupropion + minocycline' (5 mg/kg + 25 mg/kg each) were administered to mice via the intraperitoneal route. In the forced swim and tail suspension test, the immobility period was analysed after 30 min of the treatment. Monoamines like dopamine, norepinephrine and serotonin levels were analysed in brain areas such as the whole brain, hippocampus and cerebral cortex using an HPLC-fluorescence detector. Euthanasia of mice was performed 1 h after treatment. Comparison between the control group and combination therapy and other standard drug groups showed a significant decrease in immobility in both antidepressant animal models. The combination of bupropion and minocycline showed greater benefits with respect to a reduction in the immobility time period and enhancement of dopamine, serotonin, and norepinephrine levels in the cerebral cortex, hippocampus and the whole brain when compared to the monotherapy treated groups. Hence, the side effects may be reduced drastically through this combination by a reduction in the bupropion/minocycline dosage.

Potentiation of Antidepressant Effects of Agomelatine and Bupropion by Hesperidin in Mice.

Hesperidin, a well-known flavanone glycoside mostly found in citrus fruits, showed neuroprotective and antidepressant activity. Agomelatine, a melatonergic MT1/MT2 agonist and 5-HT2C receptor antagonist, exhibits good antidepressant efficacy. Bupropion has been widely used for the treatment of depression because of its dopamine and norepinephrine reuptake inhibition. The objective of present study was to assess the antidepressant effects of hesperidin combination with agomelatine or bupropion. Male Swiss Albino mice received treatment of saline, vehicle, 'hesperidin alone', 'agomelatine alone', hesperidin+agomelatine, 'bupropion alone', hesperidin+bupropion, and agomelatine+bupropion for 14 days. The immobility period was analysed 30 min after the treatment in forced swim and tail suspension tests. Dopamine and serotonin levels were analysed in hippocampus, cerebral cortex, and whole brain using HPLC with fluorescence detector. Hesperidin plus agomelatine treated group was better in terms of decrease in immobility period and increase in dopamine and serotonin levels when compared to their respective monotherapy treated groups.

Herbal approach in the treatment of pancytopenia.

Pancytopenia is a health condition in which there is a reduction in the amount of leucocytes, erythrocytes and thrombocytes. If more than one of the blood cells is low then the condition is called as bicytopenia. The pancytopenic condition is observed in treatment of diseased conditions like thalassemia and hepatitis C. Iatrogenically pancytopenia is caused by some antibiotics and anti-HCV drugs. Medical conditions like aplastic anaemia, lymphoma, copper deficiency, and so forth can also cause pancytopenia. Pancytopenia can in turn decrease the immunity of the person and thereby can be fatal. Current therapies for pancytopenia include bone marrow stimulant drugs, blood transfusion and bone marrow transplant. The current therapies are very excruciating and have long-term side-effects. Therefore, treating these condition using herbal drugs is very important. Herbs like wheatgrass, papaya leaves and garlic are effective in treating single lineage cytopenias. The present review is focused on the potential effects of natural herbs for the treatment of pancytopenia.

Evaluation of anxiolytic effects of aripiprazole and hydroxyzine as a combination in mice.

CONTEXT: Anxiety disorders are chronic, common, and often comorbid. There is an unmet need in its treatment. Aripiprazole and hydroxyzine are well-known therapeutic options used as monotherapy in clinics. They have different mechanisms and site of actions. AIM: The objective of the present study was to evaluate the anxiolytic effect of aripiprazole and hydroxyzine in combination. MATERIALS AND METHODS: Swiss albino mice (male) received treatment of 5% of Tween 80 in 0.9% saline (10 ml/kg; control group), "aripiprazole alone" (1 mg/kg), "hydroxyzine alone" (3 mg/kg), and aripiprazole (0.5 mg/kg) + hydroxyzine (1.5 mg/kg) through the intraperitoneal route. RESULTS: The in vivo outcomes (elevated plus maze, light/dark transition, and marble burying tests) of hydroxyzine monotherapy-treated group showed a significant anxiolytic activity. The combination-treated group was found to be better than control and aripiprazole-treated groups. The combination-treated group showed a significant increase in the level of serotonin in different brain regions as compared to aripiprazole-treated group but not better than the hydroxyzine group. The in vitro results were in compliance with the in vivo results. The combinational approach was found to be beneficial in anxiolytic treatment as compared to aripiprazole monotherapy. However, hydroxyzine showed better anxiolytic activity when compared to control, aripiprazole monotherapy, and combination groups. CONCLUSIONS: The anxiolytic effect of combination-treated group was found to be better than aripiprazole monotherapy and lesser than hydroxyzine monotherapy.

Effect of a combination of duloxetine with hydroxyzine on experimental models of anxiety in mice.

OBJECTIVE: There is a strong association between depression and anxiety. Duloxetine, an antidepressant agent, is also used in the treatment of anxiety. Hydroxyzine is preferred over benzodiazepines in the treatment of anxiety. Present study was designed to study the impact of a combination of duloxetine with hydroxyzine in treatment of anxiety. MATERIALS AND METHODS: Mice received intraperitoneal injection of normal saline (10 ml/kg), duloxetine alone (10 mg/kg), hydroxyzine alone (10 mg/kg), and hydroxyzine plus duloxetine (5 mg/kg, each). RESULTS: The in vivo results (elevated plus maze and light/dark transition tests) showed significant anxiolytic activity with the hydroxyzine treatment than the control group. The brain monoamines were significantly increased in hippocampi, cerebral cortices, and whole brain in drug-treated groups than in the control group. The group receiving the combination showed similar results in the in vivo models and in vitro tests (brain monoamine estimations) than respective monotherapies, with the exception of a greater increase of norepinephrine levels in cerebral cortices in duloxetine-treated group. CONCLUSION: Combination of duloxetine with hydroxyzine is not beneficial in anxiolytic treatment than the respective monotherapies. There is a need to study the pharmacokinetic drug-drug interactions to understand the present study outcomes.

Enhancement of nootropic effect of duloxetine and bupropion by caffeine in mice.

OBJECTIVE: The existing evidence suggests an association between depression and memory impairment. The objective of present study was to assess the effect of low dose caffeine with duloxetine and bupropion on memory. MATERIALS AND METHODS: Mice were divided randomly into seven groups. Intra-peritoneal treatment of normal saline (10 ml/kg), caffeine (10 mg/kg), duloxetine (10 mg/kg), bupropion alone (10 mg/kg), caffeine + duloxetine (5 mg/kg, each), caffeine + bupropion (5 mg/kg, each), and bupropion + duloxetine (5 mg/kg, each) were given to groups I-VII, respectively. Elevated plus maze was used to evaluate transfer latency (TL) and Morris water maze was used to estimate the time spent in target quadrant. RESULTS: Caffeine with duloxetine treated group was better than other combination treated groups in terms of a significant decrease in TL and increase in the time spent in target quadrant recorded. CONCLUSION: Combining lower dose of caffeine with duloxetine may enhance cognitive benefits than respective monotherapies.

The Combination of Antidepressant Duloxetine with Piracetam in Mice does not Produce Enhancement of Nootropic Activity.

There is a strong association between depression and memory impairment. The present study aims to assess the nootropic activity of duloxetine and piracetam combination. Male Swiss Albino mice were divided randomly into 4 groups. Treatment of normal saline (10 ml/kg), duloxetine (10 mg/kg), piracetam (100 mg/kg), and duloxetine (5 mg/kg) plus piracetam (50 mg/kg) were given through intra-peritoneal route to group I-IV, respectively. Transfer latency in elevated plus maze (EPM) and time spent in target quadrant in Morris water maze (MWM) were recorded. Estimation of brain monoamines in hippocampus, cerebral cortex, and whole brain were done using HPLC with fluorescence detector. Piracetam treated group showed significant decrease in transfer latency in EPM and increase in time spent in target quadrant recorded in MWM. Combination treated group failed to produce statistically significant nootropic effect in both EPM and MWM. Combination treated group failed to increase brain monoamine levels when compared against duloxetine and piracetam treated groups, separately. But there was exception of significant increase in norepinephrine levels in hippocampi when compared against duloxetine treated group. Results indicate no cognitive benefits with piracetam plus duloxetine combination. These findings can be further probed with the aim of understanding the interaction between duloxetine and piracetam as a future endeavor.

Augmentation of antidepressant effects of duloxetine and bupropion by caffeine in mice.

There is an unmet need in the treatment of depression suggesting requirement of new therapeutic approaches having better efficacy and safety profile. Patients receiving antidepressant therapy generally consume caffeine in the form of tea or coffee. The objective of the present study was to evaluate the augmentation of antidepressant effects of duloxetine and/or bupropion with caffeine. Male Swiss Albino mice received treatment of normal saline (10 ml/kg), 'caffeine alone' (10mg/kg), 'duloxetine alone' (10mg/kg), 'bupropion alone' (10mg/kg), caffeine+duloxetine (5mg/kg, each), bupropion+caffeine (5mg/kg, each), and bupropion+duloxetine (5mg/kg, each) through the intra-peritoneal route. The immobility period was analyzed 30 min after the treatment in forced swim and tail suspension tests. Norepinephrine, dopamine, and serotonin levels were analyzed in hippocampus, cerebral cortex and whole brain using HPLC with fluorescence detector. Euthanasia was performed 1h after treatment. Comparison between vehicle treated group and other groups showed significant decrease in immobility in all drug treated groups in both antidepressant models. Caffeine plus duloxetine treated group was better among the combination treated groups in terms of decrease in immobility and increase in norepinephrine, dopamine, and serotonin levels in hippocampi, cerebral cortices, and whole brain when compared to their respective monotherapy treated groups. These combination approaches may help in reducing the dose of duloxetine/bupropion, and consequently lower the associated side/adverse effects.

Impact of pre-exposure of tail suspension on behavioural parameters like locomotion, exploration, and anxiety in mice.

The tail suspension test (TST) is a valid tool for assessing antidepressant activity. Association between depression and lower locomotion and exploration activities is also reported. In the present study, photoactometer, hole board and elevated plus maze tests were performed to evaluate locomotion, exploration and anxiety activities on animals of first and second set, however animals of second set were pre-exposed to TST. The comparison between these two sets will help in understanding the impact of pre-exposure to TST on behavioural parameters. In both sets, swiss albino mice were treated with caffeine (10 mg/kg, ip), bupropion (10 mg/kg, ip), duloxetine (10 mg/kg, ip), nicotine (0.8 mg/kg, sc) and normal saline. Control group of second set showed significant decrease in locomotion, exploration and increase in anxiety when compared against control group of first set. In second set, duloxetine, bupropion, and nicotine treated groups showed significant increase in locomotion when compared against control group of same set. Overall, pre-exposure to TST leads to significant decrease in locomotion, exploration activities and increase in anxiety level. Further studies demonstrating it's time bound impact on brain monoamine levels with correlation to behavioural paradigms may help to validate these outcomes.