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Neurodegenerative disease is mainly characterized by the accumulation of misfolded proteins, contributing to mitochondrial impairments, increased production of proinflammatory cytokines and reactive oxygen species, and neuroinflammation resulting in synaptic loss and neuronal loss. These pathophysiological factors are a serious concern in the treatment of neurodegenerative diseases. Based on the symptoms of various neurodegenerative diseases, different treatments are available, but they have serious side effects and fail in clinical trials, too. Therefore, treatments for neurodegenerative diseases are still a challenge at present. Thus, it is important to study an alternative option. Capsaicin is a naturally occurring alkaloid found in capsicum. Besides the TRPV1 receptor activator in nociception, capsaicin showed a protective effect in brain-related disorders. Capsaicin also reduces the aggregation of misfolded proteins, improves mitochondrial function, and decreases ROS generation. Its antioxidant role is due to increased expression of an nrf2-mediated signaling pathway. Nrf2 is a nuclear erythroid 2-related factor, a transcription factor, which has a crucial role in maintaining the normal function of mitochondria and the cellular defense system against oxidative stress. Intriguingly, Nrf2 mediated pathway improved the upregulation of antioxidant genes and inhibition of microglial-induced inflammation, improved mitochondrial resilience and functions, leading to decreased ROS in neurodegenerative conditions, suggesting that Nrf2 activation could be a better therapeutic approach to target pathophysiology of neurodegenerative disease. Therefore, the present review has evaluated the potential role of capsaicin as a pharmacological agent for the treatment and management of various neurodegenerative diseases via the Nrf2-mediated signaling pathway.

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Estrogen replacement therapy including specific estrogen receptor alpha (ERα) agonist, 4,4′,4″-(4-propyl-[1H] pyrazole-1,3,5-triyl) trisphenol (PPT), improves cognitive function in the females with estrogen insufficiency condition. It is well suggested that the cyclic nucleotides are considered as one of the downstream mediators to ERα receptor activity and they can be hypothesized as a potential target in the management of estrogen insufficiency condition. Roflumilast, a phosphodiesterase-4 inhibitor, increases the level of cyclic adenosine monophosphate (cAMP) in most of the tissues including the brain, and is reported to have procognitive activity in the experimental animals. Hence, the present study evaluated the therapeutic effect of roflumilast with or without PPT in rats with experimentally-induced estrogen insufficiency. Estrogen insufficiency was induced in female rats through bilateral ovariectomy on day-1 (D-1) of the experimental schedule. Roflumilast (0.3 and 1.0 mg/kg; p.o.) and PPT (333µg/kg; i.p.) attenuated ovariectomy-induced cognitive deficits in the rodents during behavioral tests. Roflumilast and PPT increased the cholinergic function and cAMP level in the rat hippocampus and prefrontal cortex. Further, ovariectomy-induced decrease in the extent of phosphorylation of ERα in both the brain regions was attenuated with the monotherapy of either roflumilast or PPT. Interestingly, the combination of 1.0 mg/kg roflumilast and PPT exhibited better therapeutic effectiveness than their monotherapy. In addition, roflumilast facilitated PPT-induced increase in the level of expression of phosphorylated protein kinase-B (Akt) in both the rat brain regions. Hence, it can be assumed that the combination of roflumilast and PPT could be a therapeutic option in the management of estrogen insufficiency-induced disorders.

Background: Preclinical experimental models historically play a critical role in the exploration and characterization of disease pathophysiology. Further, these in-vivo and in-vitro preclinical experiments help in target identification, evaluation of novel therapeutic agents and validation of treatments. Introduction: Diabetes mellitus (DM) is a multifaceted metabolic disorder of multidimensional aetiologies with the cardinal feature of chronic hyperglycemia. To avoid or minimize late complications of diabetes and related costs, primary prevention and early treatment are therefore necessary. Due to its chronic manifestations, new treatment strategies need to be developed, because of the limited effectiveness of the current therapies. Methods: The study included electronic databases such as Pubmed, Web of Science and Scopus. The datasets were searched for entries of studies up to June, 2018. Results: A large number of in-vivo and in-vitro models have been presented for evaluating the mechanism of anti-hyperglycaemic effect of drugs in hormone-, chemically-, pathogen-induced animal models of diabetes mellitus. The advantages and limitations of each model have also been addressed in this review. Conclusion: This review encompasses the wide pathophysiological and molecular mechanisms associated with diabetes, particularly focusing on the challenges associated with the evaluation and predictive validation of these models as ideal animal models for preclinical assessments and discovering new drugs and therapeutic agents for translational application in humans. This review may further contribute to discover a novel drug to treat diabetes more efficaciously with minimum or no side effects. Furthermore, it also highlights ongoing research and considers the future perspectives in the field of diabetes.

Obsessive–compulsive disorder (OCD) is considered a heterogeneous anxiety disorder that includes compulsions. Celecoxib is considered an adjuvant to fluoxetine in the management of OCD in a clinical study. However, the experimental evidence is yet to be established. Therefore, the antianxiety and anticompulsive-like activity of celecoxib (20 mg/kg, orally) was evaluated in the presence or absence of fluoxetine (20 mg/kg, orally) in mice who were exposed to chronic unpredictable mild stress (CUMS) for 14 consecutive days. Seven-day treatment of celecoxib significantly attenuated the CUMS-induced anxiety in open-field, hole-board, elevated plus maze tests, and compulsion in the marble-burying test. Celecoxib significantly reversed the CUMS-induced decrease and increase in the levels of serotonin (5-HT) and its metabolite (5-hydroxyindole acetic acid) in the prefrontal cortex, and attenuated the CUMS-induced increase in the levels of inflammatory markers such as interleukin-6 and tumor necrosis factor-α, and apoptosis marker caspase-3 in the prefrontal cortex. Celecoxib also potentiated the anxiolytic, anticompulsive, serotonergic, anti-inflammatory, and antiapoptotic activity of 7-day treatment with fluoxetine in CUMS-challenged animals compared with their monotherapy. Thus, it can be speculated that the combination of an anti-inflammatory agent with selective serotonin reuptake inhibitor could be a better therapeutic option in the management of stress-related disorders including selective serotonin reuptake inhibitor-resistant OCD.