Current Neuropharmacology (v.15, #7)

Meet Our Editorial Board Member by Raymond G. Hill (937-937).

Biological Drugs in Guillain-Barré Syndrome: An Update by Nazgol Motamed-Gorji, Nassim Matin, Omidreza Tabatabaie, Piero Pavone, Catia Romano, Raffaele Falsaperla, Giovanna Vitaliti (938-950).
Background: Guillain-Barré Syndrome (GBS) is currently considered the most common global cause of acute flaccid paralysis. Currently, standard therapy for Guillain-Barré Syndrome includes intravenous immunoglobulin or plasma exchange. Despite medical advances regarding these treatments, many treated patients do not reach full recovery. Therefore several biological agents have attracted the attentions from researchers during the last decades, and various studies have investigated their role in Guillain-Barré Syndrome. <P></P> Objective: The present study aims to address emerging biological approaches to GBS while considering their efficiency and safety in treating the disease. <P></P> Materials and Methods: An extensive electronic literature search was conducted by two researchers from April 2016 to July 2016. Original articles, clinical trials, systematic reviews (with or without meta-analysis) and case reports were selected. Titles and abstracts of papers were screened by reviewers to determine whether they met the eligibility criteria, and full texts of the selected articles were retrieved. <P></P> Results: Herein authors focused on the literature data concerning emerging biological therapeutic agents, namely anti-C5 monoclonal antibody (Eculizumab), anti-C1q monoclonal antibody, anti-T cell monoclonal antibody, anti-CD2 monoclonal antibody, anti L-selectin monoclonal antibody, anti- CD20 monoclonal antibody (Rituximab), anti-CD52 monoclonal antibody (Alemtuzumab) and cytokine targets. By far, none of these agents have been approved for the treatment of GBS by FDA. <P></P> Conclusion: Literature findings represented in current review herald promising results for using these biological targets. Current review represents a summary of what is already in regards and what progress is required to improve the immunotherapeutic approach of treating GBS via future studies.

Melatonin as a Therapeutic Resource for Inflammatory Visual Diseases by Marcos L. Aranda, María Florencia González Fleitas, Hernán Dieguez, Agustina Iaquinandi, Pablo H. Sande, Damián Dorfman, Ruth E. Rosenstein (951-962).
Background: Uveitis and optic neuritis are prevalent ocular inflammatory diseases, and highly damaging ocular conditions. Both diseases are currently treated with corticosteroids, but they do not have adequate efficacy and are often associated with severe side effects. Thus, uveitis and optic neuritis remain a challenging field to ophthalmologists and a significant public health concern. <P></P> Objective: This review summarizes findings showing the benefits of a treatment with melatonin in experimental models of these inflammatory ocular diseases. <P></P> Results: Oxidative and nitrosative damage, tumor necrosis factor, and prostaglandin production have been involved in the pathogeny of uveitis and optic neuritis. Melatonin is an efficient antioxidant and antinitridergic, and has the ability to reduce prostaglandin and tumor necrosis factor levels both in the retina and optic nerve. Moreover, melatonin not only prevents functional and structural consequences of experimental uveitis and optic neuritis, but it is also capable of suppressing the actively ongoing ocular inflammatory response. <P></P> Conclusions: Since melatonin protects ocular tissues against inflammation, it could be a potentially useful anti-inflammatory therapy in ophthalmology.

Background: Ketamine has been reported to exert rapid and sustained antidepressant effects in patients with depression, including patients with treatment-resistant depression. However, ketamine has several drawbacks such as psychotomimetic/dissociative symptoms, abuse potential and neurotoxicity, all of which prevent its routine use in daily clinical practice. <P></P> Methods: Therefore, development of novel agents with fewer safety and usage concerns for the treatment of depression has been actively investigated. From this standpoint, searching for active substances (stereoisomers and metabolites) and agents acting on the N-methyl-D-aspartate (NMDA) receptor have recently gained much attention. <P></P> Results: The first approach includes stereoisomers of ketamine, (R)-ketamine and (S)-ketamine. Although (S)-ketamine has been considered as the active stereoisomer of racemic ketamine, recently, (R)-ketamine has been demonstrated to exert even more prolonged antidepressant effects in animal models than (S)-ketamine. Moreover, ketamine is rapidly metabolized into several metabolites, and some metabolites are speculated as being active substances exerting antidepressant effects. Of such metabolites, one in particular, namely, (2R,6R)-hydroxynorketamine, has been reported to be responsible for the antidepressant effects of ketamine. The second approach includes agents acting on the NMDA receptor, such as glycine site modulators and GluN2B subunit-selective antagonists. These agents have been tested in patients with treatment-resistant depression, and have been found to exhibit rapid antidepressant effects like ketamine. <P></P> Conclusion: The above approaches may be useful to overcome the drawbacks of ketamine. Elucidation of the mechanisms of action of ketamine may pave the way for the development of antidepressant that are safer, but as potent and rapidly acting as ketamine.

Objective: Obsessive-compulsive disorder (OCD) is a mental disease commonly associated with severe distress and impairment of social functioning. Serotonin reuptake inhibitors and/or cognitive behavioural therapy are the therapy of choice, however up to 40% of patients do not respond to treatment. Glutamatergic signalling has also been implicated in OCD. The aim of the current study was to review the clinical evidence for therapeutic utility of glutamate-modulating drugs as an augmentation or monotherapy in OCD patients. <P></P> Methods: We conducted a search of the MEDLINE database for clinical studies evaluating the effect of glutamate-modulating drugs in OCD. <P></P> Results: Memantine is the compound most consistently showing a positive effect as an augmentation therapy in OCD. Anti-convulsant drugs (lamotrigine, topiramate) and riluzole may also provide therapeutic benefit to some OCD patients. Finally, ketamine may be of interest due to its potential for a rapid onset of action. <P></P> Conclusion: Further randomized placebo-controlled trials in larger study populations are necessary in order to draw definitive conclusions on the utility of glutamate-modulating drugs in OCD. Furthermore, genetic and epigenetic factors, clinical symptoms and subtypes predicting treatment response to glutamate-modulating drugs need to be investigated systematically.

The Infectious Etiology of Alzheimer's Disease by Marta Sochocka, Katarzyna Zwolińska, Jerzy Leszek (996-1009).
Background: Inflammation is a part of the first line of defense of the body against invasive pathogens, and plays a crucial role in tissue regeneration and repair. A proper inflammatory response ensures the suitable resolution of inflammation and elimination of harmful stimuli, but when the inflammatory reactions are inappropriate it can lead to damage of the surrounding normal cells. The relationship between infections and Alzheimer’s Disease (AD) etiology, especially lateonset AD (LOAD) has been continuously debated over the past three decades. <P></P> Methods: This review discusses whether infections could be a causative factor that promotes the progression of AD and summarizes recent investigations associating infectious agents and chronic inflammation with AD. Preventive and therapeutic approaches to AD in the context of an infectious etiology of the disease are also discussed. <P></P> Results: Emerging evidence supports the hypothesis of the role of neurotropic viruses from the Herpesviridae family, especially Human herpesvirus 1 (HHV-1), Cytomegalovirus (CMV), and Human herpesvirus 2 (HHV-2), in AD neuropathology. Recent investigations also indicate the association between Hepatitis C virus (HCV) infection and dementia. Among bacteria special attention is focused on spirochetes family and on periodontal pathogens such as Porphyromonas gingivalis or Treponema denticola that could cause chronic periodontitis and possibly contribute to the clinical onset of AD. <P></P> Conclusion: Chronic viral, bacterial and fungal infections might be causative factors for the inflammatory pathway in AD.

Mechanisms of Melatonin in Alleviating Alzheimer's Disease by Mayuri Shukla, Piyarat Govitrapong, Parichart Boontem, Russel J. Reiter, Jutamaad Satayavivad (1010-1031).
Alzheimer’s disease (AD) is a chronic, progressive and prevalent neurodegenerative disease characterized by the loss of higher cognitive functions and an associated loss of memory. The thus far “incurable” stigma for AD prevails because of variations in the success rates of different treatment protocols in animal and human studies. Among the classical hypotheses explaining AD pathogenesis, the amyloid hypothesis is currently being targeted for drug development. The underlying concept is to prevent the formation of these neurotoxic peptides which play a central role in AD pathology and trigger a multispectral cascade of neurodegenerative processes post-aggregation. This could possibly be achieved by pharmacological inhibition of β- or γ-secretase or stimulating the nonamyloidogenic α-secretase. Melatonin the pineal hormone is a multifunctioning indoleamine. Production of this amphiphilic molecule diminishes with advancing age and this decrease runs parallel with the progression of AD which itself explains the potential benefits of melatonin in line of development and devastating consequences of the disease progression. Our recent studies have revealed a novel mechanism by which melatonin stimulates the nonamyloidogenic processing and inhibits the amyloidogenic processing of β-amyloid precursor protein (βAPP) by stimulating α -secretases and consequently down regulating both β- and γ-secretases at the transcriptional level. In this review, we discuss and evaluate the neuroprotective functions of melatonin in AD pathogenesis, including its role in the classical hypotheses in cellular and animal models and clinical interventions in AD patients, and suggest that with early detection, melatonin treatment is qualified to be an anti-AD therapy.

Background: A resurgence of neurobiological and clinical research is currently underway into the therapeutic potential of serotonergic or ‘classical’ psychedelics, such as the prototypical psychedelic drug lysergic acid diethylamide (LSD), psilocybin (4-phosphoryloxy-N,Ndimethyltryptamine), and ayahuasca – a betacarboline- and dimethyltryptamine (DMT)-containing Amazonian beverage. The aim of this review is to introduce readers to the similarities and dissimilarities between psychedelic states and night dreams, and to draw conclusions related to therapeutic applications of psychedelics in psychiatry. <P></P> Methods: Research literature related to psychedelics and dreaming is reviewed, and these two states of consciousness are systematically compared. Relevant conclusions with regard to psychedelicassisted therapy will be provided. <P></P> Results: Common features between psychedelic states and night dreams include perception, mental imagery, emotion activation, fear memory extinction, and sense of self and body. Differences between these two states are related to differential perceptual input from the environment, clarity of consciousness and meta-cognitive abilities. Therefore, psychedelic states are closest to lucid dreaming which is characterized by a mixed state of dreaming and waking consciousness. <P></P> Conclusion: The broad overlap between dreaming and psychedelic states supports the notion that psychedelics acutely induce dreamlike subjective experiences which may have long-term beneficial effects on psychosocial functioning and well-being. Future clinical studies should examine how therapeutic outcome is related to the acute dreamlike effects of psychedelics.

Background: Many prostate cancer (PCa) patients are on androgen deprivation therapy (ADT) as part of their cancer treatments but ADT may lead to cognitive impairments. ADT depletes men of both androgen and estrogen. Whether estradiol supplementation can improve cognitive impairments in patients on ADT is understudied. <P></P> Objective: To summarize data on the effects of estradiol treatment on cognitive function of androgen-deprived genetic male populations (PCa patients and male-to-female transsexuals) and castrated male animals. <P></P> Method: Publications were identified by a literature search on PubMed and Google Scholar. <P></P> Results: While some studies showed that estradiol improves cognitive function (most notably, spatial ability) for castrated rats, what remains uninvestigated are: 1) whether estradiol can improve cognition after long-term androgen deprivation, 2) how estradiol affects memory retention, and 3) how early vs. delayed estradiol treatment after castration influences cognition. For androgendeprived genetic males, estradiol treatment may improve some cognitive functions (e.g., verbal and visual memory), but the findings are not consistent due to large variability in the study design between studies. <P></P> Conclusion: Future studies are required to determine the best estradiol treatment protocol to maximize cognitive benefits for androgen-deprived genetic males. Tests that assess comparable cognitive domains in human and rodents are needed. What particularly under-investigated is how the effects of estradiol on cognitive ability intersect with other parameters; sleep, depression and physical fatigue. Such studies have clinical implications to improve the quality of life for both PCa patients on ADT as well as for male-to-female transsexuals.