BACKGROUND:Cannabinoid receptors are involved in the neuro-pathogenic mechanisms of inflammatory conditions of the central nervous system and their expression can be modulated during diseases.METHODS:In this manuscript we highlight the function of cannabinoid receptors, their signalling and expression at peripheral and central levels in order to understand their implication in neuro-inflammation and review the effects of cannabinoids in neuro-inflammatory disorders.RESULTS:Brain inflammatory processes are characterized by infiltration of numerous types of cells: both peripheral and brain resident immune cells and other neuronal cells. The disruption of the blood brain barrier favours cell infiltration in the central nervous system with consequent neuronal damage, a common event in many neuro-inflammatory diseases. Cannabinoids affect brain adaptive and immune response, regulate inflammatory mediators and can exert a role in blood brain barrier damage prevention.CONCLUSION:Various patents describe the beneficial properties of cannabinoids in numerous neurodegenerative diseases with inflammatory components and overall effects support the therapeutic application of cannabinoids.
BACKGROUND:Since the discovery of the cannabinoid receptors, numerous studies associate the endocannabinoid system with several physiological and pathological processes including cancer, appetite, fertility, memory, neuropathic and inflammatory pain, obesity, and neurodegenerative diseases. Over the last two decades, several researches have been dedicated extensively on the cannabinoid receptors ligands since the direct activation of cannabinoid receptors results in several beneficial effects, in the brain and in the periphery. The cannabinoid CB1 and CB2 receptor synthetic ligands reported in this review have been collected by a wide research of scientific literature in particular in public database for patents and clinical trials. The references for patent numbers, clinical trial registry numbers, websites and scientific articles are reported in the reference section.RESULTS:During past years, cannabinoid CB1 and CB2 receptor ligands from plants or lab were rapidly developed and then various new structures were reported to be cannabinoids. However the CB1 receptor ligands have had a limited usefulness due to their psychotropic effects, dependence, and cognitive impairment. On the contrary the development of CB2 receptor ligands has been more productive. Furthermore peripherally restricted agonists as well as CB1 receptor positive or negative allosteric modulators were studied with the aim of eliminating the undesirable CB1 receptor central effects.CONCLUSIONS:The CB1 and CB2 receptor ligands offer several therapeutic opportunities for several CNS-related diseases. Based on the scientific literature, this review provides an overview of CB1 and CB2 receptor synthetic ligands obtained from drug research and in particular those synthesized for therapeutic purposes and potential clinical applications for central nervous system disorders.
BACKGROUNDWe have recently released the structure of a class of quinolin-2-(1H)-on-3-carboxamide derivatives and among them; the drug A2 has the highest CB2 receptor selectivity.OBJECTIVEIn this work we assessed the immuno-modulatory properties of A2 in lymphocytes isolated from peripheral blood of multiple sclerosis patients and healthy donors.METHODSCell proliferative response was measured by 3H-thymidine incorporation, cell viability and apoptosis by trypan blue, annexin V staining and western blot. Cell activation was investigated by flow cytometry and molecular pathways by western blot.RESULTSA2 exerted anti-proliferative effects with down-regulation of TNF-α, IL-10 and Rantes in both cell types. No relevant changes were observed in cell viability between the two cell types. In cells from healthy subjects, A2 did not induce apoptosis, inhibited the cell cycle and similarly down-regulated in CD4+T cells the markers CD69, CD25, CD49d and CD54. Indeed, A2 also inhibited the phosphorylation of Akt, NF-kB, IKKα/β, ERK and blocked the expression of Cox-2 and CB2 receptor. Published patents also describe CB2 receptor agonists like purine derivatives. Differently, in cells from patients, A2 did not affect CD49d, while potently blocked CD54 expression. A2 inhibitory effects of Akt and Cox-2 expression were confirmed, whereas unchanged level of the CB2 receptor was observed in these cells.CONCLUSIONWe reported similar effects of A2 in both cell types; however, a different mechanism of action might be suggested in cells from patients concerning cell activation and CB2 receptor expression. Overall, these data suggest an anti-inflammatory profile of A2 with potential implication in multiple sclerosis.
BACKGROUNDAnandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are signalling lipids which belong to the class of endocannabinoids (ECs) and exert their actions by activating cannabinoid receptor type-1 (CB1) and type-2 (CB2). These receptors are involved in many physiological and pathological processes in the central nervous system (CNS) and in peripheral organs. Despite many potent and selective ligands for cannabinoid receptors have been generated over the last two decades, this class of compounds achieved only a very limited therapeutic success, mainly because of the CB1- mediated side effects.METHODSThe compounds and results presented in this review article have been gathered from an extensive research in public databases for patents, clinical trials and scientific literature. Reference to patent numbers, clinical trial registry numbers, websites and scientific articles is provided in the text and/or in the reference section.RESULTSOver the last 10-15 years, many inhibitors for the main EC hydrolytic enzymes fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), α,β-hydrolase domain-6 (ABHD6) and -12 (ABHD12) have been synthesized and characterized in vitro and in vivo. Additionally, other targets have been explored for the modulation of the endocannabinoid system (ECS). Among them, several novel inhibitors for COX-2, diacylglycerol lipases and the putative endocannabinoid membrane transporter have been described in the literature. Polypharmacological approaches which combine mild or reversible inhibition of at least two of these targets are also under investigation.CONCLUSIONSThe ECS offers several therapeutic opportunities beyond the direct activation of cannabinoid receptors. The modulation of EC levels in vivo represents an interesting therapeutic perspective for several CNS-related diseases. Based on the literature and patent literature this review provides an overview of the different classes of inhibitors for FAAH, MAGL, ABHDs and COX-2 used as tool compounds and for clinical development with a special focus on CNS-related diseases.
BACKGROUND:Several studies support the evidence that the endocannabinoid system and cannabimimetic drugs might have therapeutic potential in numerous pathologies. These pathologies range from neurological disorders, atherosclerosis, stroke, cancer to obesity/metabolic syndrome and others.METHODS:In this paper we review the endocannabinoid system signaling and its alteration in neurodegenerative disorders like multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease and discuss the main findings about the use of cannabinoids in the therapy of these pathologies.RESULTS:Despite different etiologies, neurodegenerative disorders exhibit similar mechanisms like neuro-inflammation, excitotoxicity, deregulation of intercellular communication, mitochondrial dysfunction and disruption of brain tissue homeostasis. Current treatments ameliorate the symptoms but are not curative. Interfering with the endocannabinoid signaling might be a valid therapeutic option in neuro-degeneration. To this aim, pharmacological intervention to modulate the endocannabinoid system and the use of natural and synthetic cannabimimetic drugs have been assessed. CB1 and CB2 receptor signaling contributes to the control of Ca2+ homeostasis, trophic support, mitochondrial activity, and inflammatory conditions.CONCLUSION:Several studies and patents suggest that the endocannabinoid system has neuro-protective properties and might be a target in neurodegenerative diseases.
BACKGROUND:Owing to the increasing aged population globally, disorders and diseases of the CNS are anticipated to increase and profoundly impact the health care. As these neurodegenerative diseases (NDD) are complex, multifactorial and do not have identified etiological factors, unfortunately, drugs developed for the purpose have not met with the expected success. Hence, there has been a constant demand for the development of natural therapeutic adjuvants which are safe and possess the potential to attenuate multiple pathways.METHODS:Numerous herbal/natural products have been used as therapeutics in Ayurvedic system of medicine to treat NDD and other memory-related disorders. Withania somnifera (Ashwagandha, WS), popularly called as "Indian Ginseng" is one such plant which possesses a variety of beneficial neuropharmacological properties. In this review, we have attempted to review critically the existing literature and patents related to the neuroprotective efficacy of WS roots and the underlying mechanism/s.RESULTS:Standardized extracts of Withania somnifera (WS) have been demonstrated to possess multidimensional neuromodulatory effects both in vitro and animal models. The spectrum of effects evidenced comprises of attenuation of oxidative damage by enhancing the antioxidant defense system with concomitant enhancement of the expression of marker proteins responsible for growth, differentiation and communication of neural cells. Specific effects of WS are attributable to its potential to modulate neurotrophic factors, cytoskeletal elements, cell adhesion molecules and synaptic proteins.CONCLUSION:Generation of new data by employing systematic contemporary approaches such as bioinformatics, molecular docking studies, identification of specific gene targets and epigenetic regulation would provide the necessary impetus to validate fully the neurotherapeutic potential of the phytochemicals derived from WS. More importantly, well-designed clinical trials are required to exploit the neuromodulatory propensity of WS extract/bioactives in specific neurodegenerative diseases such as AD and PD.
Agents acting via cannabinoid receptors have been widely developed; starting from the chemical structure of phytocannabinoids isolated from cannabis sativa plant, specific and selective compounds of these receptors have been produced ranging from partial to full agonists and /or antagonists endowed with different potency. The enhanced interest on developing such classes of drugs is due to the beneficial properties widely reported by both anecdotal reports and scientific studies describing the potential medicinal use of cannabinoids and their derivatives in numerous pathological conditions in both in vitro and in vivo models. The use of these drugs has been found to be of benefit in a wide number of neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases, just to mention some. In particular, being the cannabinoid CB1 receptor a central receptor expressed by neurons of the central nervous system, the attention for the treatment of neurological diseases has been mainly focused on compounds acting via this receptor, however some of these compounds has been showed to act by alternative pathways in some cases unrelated to CB1 receptors. Nonetheless, endocannabinoids are potent regulators of the synaptic function in the central nervous system and their levels are modulated in neurological diseases. In this study, we focused on endocannabinoid mechanism of action in neuronal signaling and on cannabimimetic drug potential application in neurological disorders. Finally, novel patents on cannabis-based drugs with applicability in central nervous system disorders are highlighted, to suggest future potential therapeutic utility of derivatives of this ancient plant.
BACKGROUND:Peptides are usually used to investigate regulatory networks and protein function. They can also be used in therapeutic research: They are employed both to identify and later to validate therapeutical target and in drug discovery processes. Their development enables the identification of several protein surfaces as crucial therapeutic targets and to promote the discovery of small drugs specific for these molecular interfaces.METHODS:This review was developed through the research of online content and patents related to natural and de novo designed peptides in neurological diseases studies. The effects of natural and derived peptides and/or peptidomimetic on models of neurodegenerative diseases and other neurological disorders were discussed.RESULTS:Many peptides are frequently identified as receptor antagonists, inhibitors of protein-protein interactions and several of them and/or peptide-derived compounds are commercial drugs or in clinical trials. Thus, peptide research could play a crucial role in the identification of protein ligands. Despite these favorable properties, they present low bioavailability and metabolic stability respect with traditional drugs. New synthetic strategies for limiting metabolic degradation and alternative routes of administration have been conceived to enlarge the number of peptide-based drugs in preclinical phases.CONCLUSION:Peptide-based drug discovery is an important option to address common therapeutic challenges including human neurological diseases.
Acute Ischemic stroke (IS) remains a leading cause of mortality and long-term disability. Owing to the time-constraints, only a fraction of acute IS patients receive the established and approved thrombolytic therapy and a sizeable proportion of acute IS stroke survivors remain permanently disabled. Rapid advances in various recanalization strategies have aimed at improving functional outcome and reducing mortality. Existing literature on various treatment approaches, including the evolution of various thrombolytic agents and interventional devices is presented in this review. In addition to describing intravenous drug trials, continual developments in the field of trials for interventional devices have been described. Additionally, some of the important recent patents filed for various experimental approaches are presented. We strongly believe that the recent therapeutic approaches, including endovascular interventional strategies, based on advanced neuroimaging evaluations appear to have a promising future for acute IS patients.
Osteoporotic hip fracture needs a specific approach and treatment, since elderly patients are at high risk for adverse outcomes after surgery. In particular, delirium often occurs in the peri-operative period, and it is associated with death, hospital-acquired complications, persistent cognitive impairments, poor functional recovery after surgery and increased healthcare costs. The pre-operative assessment of the risk factors for delirium improves the preventive measures. The delirium diagnostic tools should be included in the standard of orthogeriatric cure for hip fracture. Given the increasing complexity of the clinical pictures, we present a review of the available treatment options for delirium in patients with hip fracture. The metabolic pre-operative disorders and the management of co-morbid diseases are specific targets of treatment in order to optimize the outcomes after surgery. In particular, elderly patients with Alzheimer's disease are highly vulnerable to hip fracture and delirium, and they are severely frail with reduced physiologic reserves. An integrated approach combining environmental and pharmacological strategies is useful in the delirium treatment, with a close collaboration between the orthopedic and geriatric team.
Pharmaceutical patenting involves writing claims based on both discoveries already made, and on prophesy of future developments in an ongoing project. This is necessitated by the very different timelines involved in the drug discovery and product development process on the one hand, and successful patenting on the other. If patents are sought too early there is a risk that patent examiners will disallow claims because of lack of enablement. If patenting is delayed, claims are at risk of being denied on the basis of existence of prior art, because the body of relevant known science will have developed significantly while the project was being pursued. This review examines the role of prophetic patenting in relation to the essential predictability of many aspects of drug discovery science, promoting the concepts of discipline-related and project-related prediction. This is especially directed towards patenting activities supporting commercialization of academia-based discoveries, where long project timelines occur, and where experience, and resources to pay for patenting, are limited. The need for improved collaborative understanding among project scientists, technology transfer professionals in, for example, universities, patent attorneys, and patent examiners is emphasized.
Exosomes are small extracellular vesicles (30-120 nm) of endosomal origin, which are gaining the attention of the scientific community. Originally considered only a waste disposal system, they are now emerging as another class of signal mediators. Exosomes are secreted by any cell type and retrieved in every body fluid, such as blood, urine, saliva and amniotic liquid. Remarkably, their biochemical content includes not only lipids and proteins, but also nucleic acids, mainly miRNA and mRNA, with a few reports also indicating the presence of genomic and mitochondrial DNA. Their properties have stimulated extensive research to exploit them as a source of biomarkers for the diagnosis and the follow-up of several pathologies. Furthermore, exosomes are relatively robust and stable, so they appear attractive as gene and drug delivery vehicles. They have also revealed immunomodulatory and regenerative properties, which are encouraging their application for therapeutic purposes. Several issues remain to be addressed: exosome isolation is still time consuming and unsatisfactorily reproducible, making it difficult to compare results among laboratories, improve our knowledge of their physiological function and correlate their features with pathological outcomes. Nevertheless, the number of patents trying to address these problems is growing exponentially and many novelties will reach the scientific community in the next few years.
Tinnitus, a disorder with disruptive sound perception in the head without an external source, affects around 15 % of the worldwide adult population. Since there is no approved drug for the treatment for this symptom, novel strategies need to be developed to provide relief for the patient. A patent from the small French start-up company Sensorion suggests the use of histamine H4 receptor (H4R) inhibitors as potential treatment. Since histamine and its receptor subtypes are strongly involved in neuronal and inflammatory processes in vestibular areas, targeting the H4R could be a novel way to gain a treatment for tinnitus. Although mRNA and protein levels of H4R have been demonstrated on isolated spiral ganglion neurons from mice, the methods of receptor detection as well as the species relevance of the data are under discussion and require considerable further verification, especially on a disease with a high medical need like tinnitus.
Pleiotrophin (PTN) and Midkine (MK) are neurotrophines with documented protective actions in experimental models of neurodegenerative diseases and beneficial effects on toxicity and addictive behaviours related to drug abuse. Concerning the latter, both PTN and MK prevent the neurotoxic effects of amphetamine on nigrostriatal pathways and endogenous PTN also limits amphetamine reward. Moreover, endogenous PTN overexpression in the prefontral cortex abolishes alcohol- induced conditioned place preference. This review summarizes the existing patents for using PTN and MK in the treatment and diagnosis of neuropsychiatric disorders with a focus on neurotoxicity, neurodegeneration and substance use disorders. We have also reviewed the mechanism of action of PTN and MK and summarized existing patents on downstream modulators in their signaling pathways for the same indications.
Today, the 'obesity pandemic' is one of the biggest health issues around the world. Melanin-concentrating hormone (MCH), a hypothalamic neuropeptide, is one of the most potent, central stimulators of feeding and it also attenuates energy expenditure. Inhibitions of the MCH receptor, the melanin-concentrating hormone receptor-1 (MCHR1), has attracted considerable attention as a potential anti-obesity drug, during the last decade. Now, there are a large number of MCHR1 antagonists, pharmacological tools and clinical drug candidates that can provide clues to develop new structures with high potency and good pharmacokinetic profile. The function of MCHR1 in energy homeostasis, obesity, metabolic syndrome, mood disorders and inflammatory bowel disease is discussed. Relevant clinical trials and patent background information of the MCHR1 antagonists over the last 4 years are also reviewed.
