Current Neuropharmacology - Volume 19, Issue 7, 2021

The neuroinflammatory hypothesis of Alzheimer’s disease (AD) was proposed more than 30 years ago. The involvement of the two main types of glial cells microglia and astrocytes, in neuroinflammation, was suggested early on. In this review, we highlight that the exact contributions of reactive glia to AD pathogenesis remain difficult to define, likely due to the heterogeneity of glia populations and alterations in their activation states through the stages of AD progression. In the case of microglia, it is becoming apparent that both beneficially and adversely activated cell populations can be identified at various stages of AD, which could be selectively targeted to either limit their damaging actions or enhance beneficial functions. In the case of astrocytes, less information is available about potential subpopulations of reactive cells; it also remains elusive whether astrocytes contribute to the neuropathology of AD by mainly gaining neurotoxic functions or losing their ability to support neurons due to astrocyte damage. We identify L-type calcium channel blocker, nimodipine, as a candidate drug for AD, which potentially targets both astrocytes and microglia. It has already shown consistent beneficial effects in basic experimental and clinical studies. We also highlight the recent evidence linking peripheral inflammation and neuroinflammation. Several chronic systemic inflammatory diseases, such as obesity, type 2 diabetes mellitus, and periodontitis, can cause immune priming or adverse activation of glia, thus exacerbating neuroinflammation and increasing risk or facilitating the progression of AD. Therefore, reducing peripheral inflammation is a potentially effective strategy for lowering AD prevalence.

Cholecystokinin (CCK), the most abundant brain neuropeptide, is involved in relevant behavioral functions like memory, cognition, and reward through its interactions with the opioid and dopaminergic systems in the limbic system. CCK excites neurons by binding two receptors, CCK1 and CCK2, expressed at low and high levels in the brain, respectively. Historically, CCK2 receptors have been related to the induction of panic attacks in humans. Disturbances in brain CCK expression also underlie the physiopathology of schizophrenia, which is attributed to the modulation by CCK1 receptors of the dopamine flux in the basal striatum. Despite this evidence, neither CCK2 receptor antagonists ameliorate human anxiety nor CCK agonists have consistently shown neuroleptic effects in clinical trials. A neglected aspect of the function of brain CCK is its neuromodulatory role in mental disorders. Interestingly, CCK is expressed in pivotal inhibitory interneurons that sculpt cortical dynamics and the flux of nerve impulses across corticolimbic areas and the excitatory projections to mesolimbic pathways. At the basal striatum, CCK modulates the excitability of glutamate, the release of inhibitory GABA, and the discharge of dopamine. Here we focus on how CCK may reduce rather than trigger anxiety by regulating its cognitive component. Adequate levels of CCK release in the basal striatum may control the interplay between cognition and reward circuitry, which is critical in schizophrenia. Hence, it is proposed that disturbances in the excitatory/ inhibitory interplay modulated by CCK may contribute to the imbalanced interaction between corticolimbic and mesolimbic neural activity found in anxiety and schizophrenia.

It has been well established that there is a connection between type II diabetes (DMTII) and Alzheimer's disease (AD). In fact, the increase in AD incidence may be an emerging complication of DMTII. Both pathologies are related to estradiol (E2) exposure; on the one hand, estrogen receptors (ER) are emerging as important modulators of glucose homeostasis through ß-pancreatic cell function; on the other hand, brain bioenergetic and cognitive deficits have been related to the down regulation of brain ERs, contributing to women ageing and AD susceptibility, both related to the reduction in estradiol levels and the deficits in brain metabolism. Here we discuss that environmental contaminants with estrogenic capacity such as bisphenol A (BPA) could develop pharmacological effects similar to those of E2, which could affect ß-pancreatic cell function by increasing the biosynthesis of glucose-induced insulin after extranuclear ER binding. BPA-induced hyperinsulinemia would promote the translocation of glucose transporter 4 (GLUT4), which is located next to insulin-regulated aminopeptidase (IRAP) in intracellular vesicles. In insulin-responsive tissues, IRAP and GLUT 4 are routed together to the cell surface after insulin stimulation. IRAP is also the angiotensin IV (AngIV) receptor, and AngIV associates the brain renin-angiotensin system (bRAS) with AD, since AngIV is related to learning, memory, emotional responses, and processing of sensory information not only through its inhibitory effect on IRAP but also through the stimulation of glucose uptake by increasing the presence of IRAP/GLUT4 at the cell surface. Thus, the IRAP/GLUT4 pathway is an emerging target for pharmacological intervention against AD.

Huntington’s disease (HD) is an autosomal fatal genetic disease in which degeneration of neuronal cells occurs in the central nervous system (CNS). Commonly used therapeutics are cludemonoamine depletors, antipsychotics, antidepressants, and tranquilizers. However, these drugs cannot prevent the psychotic, cognitive, and behavioral dysfunctions associated with HD. In addition to this, their chronic use is limited by their long-term side effects. Herbal drugs offer a plausible alternative to this and have shown substantial therapeutic effects against HD. Moreover, their safety profile is better in terms of side effects. However, due to limited drug solubility and permeability to reach the target site, herbal drugs have not been able to reach the stage of clinical exploration. In recent years, the paradigm of research has been shifted towards the development of herbal drugs based nanoformulations that can enhance their bioavailability and blood-brain barrier permeability. The present review covers the pathophysiology of HD, available biomarkers, phytomedicines explored against HD, ongoing clinical trials on herbal drugs exclusively for treating HD and their nanocarriers, along with their potential neuroprotective effects.

The human digestive system is embedded with trillions of microbes of various species and genera. These organisms serve several purposes in the human body and exist in symbiosis with the host. Their major role is involved in the digestion and conversion of food materials into many useful substrates for the human body. Apart from this, the gut microbiota also maintains healthy communication with other body parts, including the brain. The connection between gut microbiota and the brain is termed as gut-brain axis (GBA), and these connections are established by neuronal, endocrine and immunological pathways. Thus, they are involved in neurophysiology and neuropathology of several diseases like Parkinson’s disease (PD), Alzheimer’s disease (AD), depression, and autism. There are several food supplements such as prebiotics and probiotics that modulate the composition of gut microbiota. This article provides a review about the role of gut microbiota in depression and supplements such as probiotics that are useful in the treatment of depression.

Curcumin is a spice derived nutraceutical which gained tremendous attention because of its profound medicinal values. It alters a number of molecular pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF128;ΚB), signal transducer and activator of transcription 3 (STAT3), nuclear factor erythroid 2-related factor 2 (Nrf2) and cyclooxygenases-2 (COX128;2), which make it potential therapeutic choice in treating multiple disorders. It also possesses the potential to prevent protein aggregation and thus protect against degeneration of neurons in neurodegenerative disorders including Huntington’s disease (HD). HD is an autosomal dominant disorder linked with altered gene expression which leads to an increase in the size of cytosine, adenine and guanine (CAG) trinucleotide repeats, aids in protein aggregation throughout the brain and thus damages neurons. Upstream regulation of oxidative stress and inflammatory cascade are two important factors that drive HD progression. Available therapies just suppress the severity of symptoms with a number of side effects. Curcumin targets multiple mechanisms in treating or preventing HD including antioxidant and anti-inflammatory potential, metal ion chelation, transcriptional alterations and upregulating activity of molecular chaperons, heat shock proteins (HSPs). Having a favorable safety profile, curcumin can be an alternative therapeutic choice in treating neurodegenerative disorders like HD. This review will focus on mechanistic aspects of curcumin in treating or preventing HD and its potential to arrest disease progression and will open new dimensions for safe and effective therapeutic agents in diminishing HD.

Neurodegeneration is a complex neurological phenomenon characterized by disturbed coherence in neuronal efflux. Progressive neuronal loss and brain damage due to various age-related pathological hallmarks perturb the behavioral balance and quality of life. Sirtuins have been widely investigated for their neuroprotective role, with SIRT1 being the most contemplated member of the family. SIRT1 exhibits significant capabilities to enhance neurogenesis and cellular lifespan by regulating various pathways, which makes it an exciting therapeutic target to inhibit neurodegenerative disease progression. SIRT1 mediated neuronal fortification involves modulation of molecular co-factors and biochemical pathways responsible for the induction and sustenance of pro-inflammatory and pro-oxidative environment in the cellular milieu. In this review, we present the major role played by SIRT1 in maintaining cellular strength through the regulation of genomic stability, neuronal growth, energy metabolism, oxidative stress, inhibiting mechanisms and anti-inflammatory responses. The therapeutic significance of SIRT1 has been put into perspective through a comprehensive discussion about its ameliorating potential against neurodegenerative stimuli in a variety of diseases that characteristically impair cognition, memory and motor coordination. This review enhances the acquaintance concerned with the neuroprotective potential of SIRT1 and thus promotes the development of novel SIRT1 regulating therapeutic agents and strategies.

Neurodegenerative diseases are characterized by the increasing dysfunction and death of neurons, resulting in progressive impairment of a person’s mobility and/or cognition. Protein misfolding and aggregation are commonly hypothesized to cause neurotoxicity and, eventually, neuronal degeneration that are associated with these diseases. Emerging experimental evidence, as well as recent findings from human studies, reveal that the C-terminus of Hsp70 Interacting Protein (CHIP), or STIP1 Homology and U-box containing Protein 1 (STUB1), is a quality control protein involved in neurodegeneration. Here, we review evidence that CHIP interacts with and plays a role in regulating proteins implicated in the pathogenesis of Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and polyglutamine diseases, including Huntington’s disease and spinocerebellar ataxias. We also review clinical findings identifying mutations in STUB1 as a cause of both autosomal recessive and autosomal dominant forms of cerebellar ataxia. We propose that CHIP modulation may have therapeutic potential for the treatment of multiple neurodegenerative diseases.

Glutamate’s role as the major excitatory neurotransmitter of the mammalian central nervous system requires that its brain concentrations be kept tightly-controlled. However, in hepatic encephalopathy resulting from liver dysfunction; disruption of central neurotransmission and elevation of brain glutamate levels have been observed. These had been associated with certain neurological changes. While neurological changes resulting from hepatic encephalopathy are believed to be transient, the discovery of alterations in liver enzymes in Alzheimer’s disease and the role of glutamate and glutamate homeostasis in hepatic encephalopathy have piqued interests in the possible role of glutamate, and glutamate homeostasis in neurodegenerative diseases. Here, we discuss the evidence in support of the involvement of peripheral/central glutamate homeostasis in the development of neurodegenerative disorders, as well as, the implications of such interactions in the development of new therapies for neurodegenerative disorders.

Migraine is a common chronic neurovascular disease characterized by headaches. Calcitonin gene-related peptide (CGRP) signaling in the trigeminovascular system plays a critical role in the development of migraine. The monoclonal antibodies against CGRP and its receptor have been used clinically for the prevention of migraine; however, they may not be a cost-effective option for patients with low-frequency episodic migraine. Thus, it is quite valuable to search for an alternative strategy to downregulate CGRP signaling. Uncariae Ramulus Cum Uncis (UR) has a longterm history for the treatment of cardiovascular and central nervous systems disorders in China and Eastern Asia. Several clinical studies showed that famous herbal formulas comprising UR were able to improve headaches in migraineurs. In addition, increasing in vivo studies further indicated that migraine-related changes, such as CGRP increase, inflammation, nitric oxide increase, and spontaneous behavior problems could be reduced by UR extraction and its active constituents. In this review, we summarize the pathophysiological factors affecting abnormal CGRP release in the trigeminovascular system during a migraine, and for the first time, analyze the effects of UR on these factors and evaluate the potentials of UR for the treatment of migraine.

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by repetitive behaviours, cognitive rigidity/inflexibility, and social-affective impairment. Unfortunately, no gold-standard treatments exist to alleviate the core socio-behavioural impairments of ASD. Meanwhile, the prosocial empathogen/entactogen 3,4-methylene-dioxy-methamphetamine (MDMA) is known to enhance sociability and empathy in both humans and animal models of psychological disorders. Objective: We review the evidence obtained from behavioural tests across the current literature, showing how MDMA can induce prosocial effects in animals and humans, where controlled experiments were able to be performed. Methods: Six electronic databases were consulted. The search strategy was tailored to each database. Only English-language papers were reviewed. Behaviours not screened in this review may have affected the core ASD behaviours studied. Molecular analogues of MDMA have not been investigated. Results: We find that the social impairments may potentially be alleviated by postnatal administration of MDMA producing prosocial behaviours in mostly the animal model. Conclusion: MDMA and/or MDMA-like molecules appear to be an effective pharmacological treatment for the social impairments of autism, at least in animal models. Notably, clinical trials based on MDMA use are now in progress. Nevertheless, larger and more extended clinical studies are warranted to prove the assumption that MDMA and MDMA-like molecules have a role in the management of the social impairments of autism.