Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 15, Issue 2, 2015

Marine animals represent a source of novel bioactive compounds considered as a good research model, whose mechanism of action is intriguing and still under debate. Among stinging animals, Cnidarians differentiated highly specialized cells, termed nematocytes, containing a capsule fluid with toxins and an inverted tubule, synergistically responsible for mechanisms of defence and predation. Such compounds include proteins and secondary metabolites with toxic action. With the aim of better elucidating the effects of Cnidarian venom upon cell targets, this short review reports on the current knowledge about the toxicological activity of venom extracted from nematocysts of the jellyfish Pelagia noctiluca, whose notable blooming is well known in the Strait of Messina (Italy). The effects on cultured cells, from both mammals and invertebrates, and erythrocytes are here being considered. What is known about the biological activity of Pelagia noctiluca crude venom accounts for a powerful biological activity at different levels, suggesting that cell damage may be due to a pore formation mechanism on cell membrane target leading to osmotic lysis, and /or to oxidative stress events. In this light, the study of venom activity may contribute to: i) validate suitable biological assays for venom testing; ii) elucidate cell function features; iii) understand the pathophysiology of envenoming.

Cnidarians are numbered among the most venomous organisms. Their venoms are contained in intracellular capsules, nematocysts, which inject the content into preys/attackers through an eversion system resembling a syringe needle. Several cnidarian venoms have activity against the nervous system, being neurotoxic, or affect other systems whose functioning is under nerve control. Besides direct damage to nerve cells, the activity on ionic conductance, blockade of neuromuscular junctions, and influence on action potentials and on voltage-gated channels have been described. Therefore, cnidarians can be a useful source of nervous system-targeted compounds which could have, in perspective, a role in the therapy of some nervous system diseases. Following this idea, this article aims to review the existing data about the neuroactive properties of cnidarian venoms and their possible usefulness in tackling some neurological diseases as well as neurodegenerative age-related diseases whose incidence is expected to raise in the next decades owing to the increase of life expectancy.

Scyphomedusae (Phylum Cnidaria, Class Scyphozoa) are perceived as a nuisance due to their sudden outbreaks that negatively affect human activities (particularly tourism and fisheries) mainly because of their stings. A brief review of the history of scyphozoan blooms in the Mediterranean and updated information available after 2010 point to an increase in scyphozoan outbreaks. Whilst the negative effects on public health, aquaculture, coastal industrial activities and fisheries operations are undeniable, the effects on the ecosystem are not well defined. We focus on the trophic interactions between scyphomedusae and fish, highlighting that the negative effects of scyphomedusae on fish stocks exerted through direct predation on early life stages of fish and competition for plankton are at present speculative. In favor of a positive effect of scyphomedusae on fish populations, the reports of predation upon scyphozoans are increasing, which suggests that predators may benefit from the availability of scyphozoans by shifting their diet toward jelly prey. Additionally, scyphomedusae may provide nursery habitats to early life stages of ecologically and economically important forage fishes and other organisms which shelter underneath their bells. Together with these ecosystem services, compounds extracted from scyphozoan tissues and venoms are having a variety of biomedical applications and are likely to contribute to treat a growing number of diseases, including cancer. Our analysis highlights that a re-evaluation of the balance between "positive" and "negative" effects of scyphomedusae on the ecosystem and human activities is needed and provides indications on potential directions for future studies.

The sea anemones (Cnidaria) produce neurotoxins, polypeptides active on voltage-gated sodium channels, which induce a non-inactivating condition, with consequent seizures and paralysis in zebrafish (Danio rerio). In humans, severe myoclonic epilepsy of infancy (SMEI) is due to SCN1A gene mutation, which causes a non-inactivating sodium channels condition with seizures. Some symptoms, such as age of first seizure, repetitive events, frequent status epilepticus, scarce responsiveness to antiepileptic drugs (AEDs), may be due to superimposed environmental causes. The authors report a case of SMEI treated for years with benzodiazepines and subsequently with valproate. The attenuation of the frequency of epileptic events and of time in seizing, but no change in burst duration and EEG events was observed. These results are similar to those reported in the literature about zebrafish scn1Lab mutant, which recapitulates the SCN1A symptoms and AED resistance occurring in humans. During seizures the production of polypeptides similar to sea anemones neurotoxins, causing repetitive seizures, status epilepticus, and AED resistance can be hypothesized in subjects with SCN1A mutation.

The chemical process initiated by QIAPI 1 has been deemed to be the most important biological reaction associated with human photosynthesis, and possibly neuroprotective effects under various inflammatory events. However, the detailed biological activities of QIAPI 1 as a melanin precursor are still unknown. In the present work, cytotoxicity test was done by MTT assay to determine cell viability of various cell lines (WI-38, A549, HS 683) like proliferation tests and its effect on cytokine production. Arsenic poisoning is an often-unrecognized cause of renal insufficiency. No prophylactic and/or therapeutic compounds have shown promising results against kidney diseases. The pathogenesis of Arsenicinduced nephropathy is not clear. Arsenic, as itself, does not degrade over time in the environment, and its accumulation may induce toxic effects. In this study, we also report the histological findings of the kidney in 3 groups of Wistar rats, a control group, a group exposed to arsenic in the water; and a group exposed to arsenic and treated with QIAPI 1 simultaneously. The findings of the current evidence indicates a potential therapeutic ability of QIAPI 1.

Parkinson’s Disease (PD) and alpha synucleinopathies are multifactorial disorders, which manifest through motor symptoms and non-motor symptoms involving the Central Nervous System (CNS), the Peripheral Nervous System (PNS) and, recently, also the Enteric Nervous System (ENS). The typical hallmarks of alpha synucleinopathies are proteinaceous inclusions of alpha synuclein (αS). In PD they are known as Lewy Bodies (LBs) and Lewy Neurites (LNs), discovered in dopaminergic neurons of substantia nigra (pars compacta) as well as in other regions of the central and peripheral nervous systems. Despite the clear causes which lead to LBs/LNs are still unknown, according to Braak’s theory, these inclusions appear first in PNS to spread, following neuronal innervation, towards the CNS in a spatio- temporal dissemination described in a staging procedure. In line with these observations, several animal models have been used with the purpose to reproduce PD as well as to propose new therapeutic approaches. Different pathways can cooperate to neurodegeneration in PD such as genetic mutations of αS gene, mitochondrial dysfunctions, neuroinflammation. The present review highlights αS as the key-word for PD pathology and alpha synucleinopathies and a main target in PD research. Several therapeutic approaches can be proposed, however all of them are addressed in advanced stages of the pathology. Our focus will be the alteration of αS physiological pathway, which allows to address therapy in early stages at intracellular or extracellular level, such as the use of anti ER-stress compounds and innovative immunotherapy, which could be promising tools to reduce neuronal degeneration and to halt PD progression.

Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterised clinically by a progressive decline in executive functions, memory and cognition. Classic neuropathological hallmarks of AD include intracellular hyper-phosphorylated tau protein which forms neurofibrillary tangles (NFT), and extracellular deposits of amyloid β (Aβ) protein, the primary constituent of senile plaques (SP). The gradual process of pathogenic amyloid accumulation is thought to occur 10-20 years prior to symptomatic manifestation. Advance detection of these deposits therefore offers a highly promising avenue for prodromal AD diagnosis. Currently, the most sophisticated method of ‘probable AD’ diagnosis is via neuroimaging or cerebral spinal fluid (CSF) biomarker analysis. Whilst these methods have reported a high degree of diagnostic specificity and accuracy, they fall significantly short in terms of practicality; they are often highly invasive, expensive or unsuitable for large-scale population screening. In recent years, ocular screening has received substantial attention from the scientific community due to its potential for non-invasive and inexpensive central nervous system (CNS) imaging. In this appraisal we build upon our previous reviews detailing ocular structural and functional changes in AD (Retinal manifestations of Alzheimer’s disease, Alzheimer’s disease and Retinal Neurodegeneration) and consider their use as biomarkers. In addition, we present an overview of current advances in the use of fluorescent reporters to detect AD pathology through non-invasive retinal imaging.

Malignant glioma is the most prevalent and lethal primary brain tumor. Due to molecular heterogeneity and organ-specific clinical manifestations, it is essential to improve glioma treatment by shifting from conventional cytotoxic chemotherapy to more targeted therapies. Hence, innovative approaches based on ligands able to specifically detect and measure mutated proteins associated to a specific tumor phenotype are needed in order to refine diagnosis and therapy of glioma. To date, antibody- based approaches have been developed for in vivo applications but, in most cases, they show toxicity, do not reach adequate sensitivity and have a low permeability across the blood-brain-barrier. Single-stranded nucleic acid aptamers, generated by the SELEX (Systematic Evolution of Ligands by EXponential enrichment) process, have been shown as a valuable alternative to protein antibodies because may couple the advantages of their chemical nature to the high specific binding of antibodies to their proper targets. The simplicity of aptamers selection and derivatization with other molecules (nanocarriers, tracers for imaging, drugs) combined to low immunogenicity and toxicity, render them a versatile tool for identification of new biomarkers, in vitro diagnosis, in vivo imaging and targeted therapy. Aim of this review article is to discuss contemporary applications of aptamers as innovative tools for glioma diagnosis and therapy. We will describe promising new approaches for the identification of aptamers targeting proteins with a crucial role in glioma, including SELEX protocols against living glioma cells and brain tumor-initiating cells. Additionally, we will review recently proposed aptamer-based strategies for site-targeted controlled delivery of therapeutics and imaging agents to the brain. Summarizing, we hope that this article will provide an updated overview of perspectives and challenges for aptamer-based glioma treatment in the near future.