scholarly journals Phytocannabinoids in Neurological Diseases: Could They Restore a Physiological GABAergic Transmission?

2020 ◽  
Vol 21 (3) ◽  
pp. 723 ◽  
Author(s):  
Pierangelo Cifelli ◽  
Gabriele Ruffolo ◽  
Eleonora De Felice ◽  
Veronica Alfano ◽  
Erwin Alexander van Vliet ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Neurological Diseases ◽  
Chloride Ion ◽  
Gaba Release ◽  
New Class ◽  
Inhibitory Function ◽  
Acid Type ◽  
Wide Range ◽  
The Central Nervous System ◽  
Neurological Conditions

γ-Aminobutyric acid type A receptors (GABAARs) are the main inhibitory mediators in the central nervous system (CNS). GABAARs are pentameric ligand gated ion channels, and the main subunit composition is usually 2α2βγ, with various isotypes assembled within a set of 19 different subunits. The inhibitory function is mediated by chloride ion movement across the GABAARs, activated by synaptic GABA release, reducing neuronal excitability in the adult CNS. Several studies highlighted the importance of GABA-mediated transmission during neuro-development, and its involvement in different neurological and neurodevelopmental diseases, from anxiety to epilepsy. However, while it is well known how different classes of drugs are able to modulate the GABAARs function (benzodiazepines, barbiturates, neurosteroids, alcohol), up to now little is known about GABAARs and cannabinoids interaction in the CNS. Endocannabinoids and phytocannabinoids are lately emerging as a new class of promising drugs for a wide range of neurological conditions, but their safety as medication, and their mechanisms of action are still to be fully elucidated. In this review, we will focus our attention on two of the most promising molecules (Δ9-tetrahydrocannabinol; Δ9-THC and cannabidiol; CBD) of this new class of drugs and their possible mechanism of action on GABAARs.

scholarly journals Dissecting the Molecular Determinants of GABAA Receptors Current Rundown, a Hallmark of Refractory Human Epilepsy

2021 ◽  
Vol 11 (4) ◽  
pp. 441
Author(s):  
Pierangelo Cifelli ◽  
Silvia Di Angelantonio ◽  
Veronica Alfano ◽  
Alessandra Morano ◽  
Eleonora De Felice ◽  
...  
Keyword(s):  
Gabaa Receptors ◽  
Drug Resistant ◽  
Human Embryonic Kidney Cells ◽  
Inhibitory Function ◽  
Human Epilepsy ◽  
Wide Range ◽  
Molecular Determinants ◽  
The Central Nervous System ◽  
Heterologous Expression Systems ◽  
Important Therapeutic Target

GABAA receptors-(Rs) are fundamental for the maintenance of an efficient inhibitory function in the central nervous system (CNS). Their dysfunction is associated with a wide range of CNS disorders, many of which characterized by seizures and epilepsy. Recently, an increased use-dependent desensitization due to a repetitive GABA stimulation (GABAA current rundown) of GABAARs has been associated with drug-resistant temporal lobe epilepsy (TLE). Here, we aimed to investigate the molecular determinants of GABAA current rundown with two different heterologous expression systems (Xenopus oocytes and human embryonic kidney cells; HEK) which allowed us to manipulate receptor stoichiometry and to study the GABAA current rundown on different GABAAR configurations. To this purpose, we performed electrophysiology experiments using two-electrode voltage clamp in oocytes and confirming part of our results in HEK. We found that different degrees of GABAA current rundown can be associated with the expression of different GABAAR β-subunits reaching the maximum current decrease when functional α1β2 receptors are expressed. Furthermore, the blockade of phosphatases can prevent the current rundown observed in α1β2 GABAARs. Since GABAAR represents one important therapeutic target in the treatment of human epilepsy, our results could open new perspectives on the therapeutic management of drug-resistant patients showing a GABAergic impairment.

scholarly journals The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration

2020 ◽  
Author(s):  
Paymaan Jafar-nejad ◽  
Berit Powers ◽  
Armand Soriano ◽  
Hien Zhao ◽  
Daniel A Norris ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Muscular Atrophy ◽  
Neurological Diseases ◽  
Cell Types ◽  
Rnase H ◽  
Central Administration ◽  
Spinal Motor Neurons ◽  
New Class ◽  
Wide Range ◽  
Therapeutic Development

Abstract Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and target RNA reduction throughout the CNS in neurons, oligodendrocytes, astrocytes and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.

scholarly journals Epigenetic Regulation of Cannabinoid-Mediated Attenuation of Inflammation and Its Impact on the Use of Cannabinoids to Treat Autoimmune Diseases

2021 ◽  
Vol 22 (14) ◽  
pp. 7302
Author(s):  
Bryan Latrell Holloman ◽  
Mitzi Nagarkatti ◽  
Prakash Nagarkatti
Keyword(s):  
Autoimmune Diseases ◽  
Chronic Inflammation ◽  
Cannabinoid Receptors ◽  
T Regulatory Cells ◽  
Neurological Diseases ◽  
Suppressor Cells ◽  
The Body ◽  
New Class ◽  
Wide Range ◽  
Clinical Disorders

Chronic inflammation is considered to be a silent killer because it is the underlying cause of a wide range of clinical disorders, from cardiovascular to neurological diseases, and from cancer to obesity. In addition, there are over 80 different types of debilitating autoimmune diseases for which there are no cure. Currently, the drugs that are available to suppress chronic inflammation are either ineffective or overtly suppress the inflammation, thereby causing increased susceptibility to infections and cancer. Thus, the development of a new class of drugs that can suppress chronic inflammation is imperative. Cannabinoids are a group of compounds produced in the body (endocannabinoids) or found in cannabis (phytocannabinoids) that act through cannabinoid receptors and various other receptors expressed widely in the brain and immune system. In the last decade, cannabinoids have been well established experimentally to mediate anti-inflammatory properties. Research has shown that they suppress inflammation through multiple pathways, including apoptosis and inducing immunosuppressive T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Interestingly, cannabinoids also mediate epigenetic alterations in genes that regulate inflammation. In the current review, we highlight how the epigenetic modulations caused by cannabinoids lead to the suppression of inflammation and help identify novel pathways that can be used to target autoimmune diseases.

scholarly journals CHIP as a therapeutic target for neurological diseases

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Shuo Zhang ◽  
Zheng-wei Hu ◽  
Cheng-yuan Mao ◽  
Chang-he Shi ◽  
Yu-ming Xu
Keyword(s):  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Neurological Diseases ◽  
Critical Role ◽  
Interacting Protein ◽  
Ubiquitin E3 Ligase ◽  
Promising Therapeutic Target ◽  
Wide Range ◽  
Range Of Functions ◽  
The Central Nervous System

Abstract Carboxy-terminus of Hsc70-interacting protein (CHIP) functions both as a molecular co-chaperone and ubiquitin E3 ligase playing a critical role in modulating the degradation of numerous chaperone-bound proteins. To date, it has been implicated in the regulation of numerous biological functions, including misfolded-protein refolding, autophagy, immunity, and necroptosis. Moreover, the ubiquitous expression of CHIP in the central nervous system suggests that it may be implicated in a wide range of functions in neurological diseases. Several recent studies of our laboratory and other groups have highlighted the beneficial role of CHIP in the pathogenesis of several neurological diseases. The objective of this review is to discuss the possible molecular mechanisms that contribute to the pathogenesis of neurological diseases in which CHIP has a pivotal role, such as stroke, intracerebral hemorrhage, Alzheimer’s disease, Parkinson’s disease, and polyglutamine diseases; furthermore, CHIP mutations could also cause neurodegenerative diseases. Based on the available literature, CHIP overexpression could serve as a promising therapeutic target for several neurological diseases.

scholarly journals Limbic system

2021 ◽  
Vol 8 (3) ◽  
pp. 01-04
Author(s):  
Modhi Alhussinan
Keyword(s):  
Human Brain ◽  
Limbic System ◽  
Functional Organization ◽  
Neurological Diseases ◽  
Emotional Responses ◽  
Wide Range ◽  
Range Of Functions ◽  
Neurological Conditions ◽  
And Function ◽  
Crucial Part

The limbic system forms a crucial part of the human brain. It is a network of structures that set beneath temporal lobe and on both sides of thalamus. It has a wide range of functions which mainly involve in our behavioral and emotional responses. Therefore, any disruption to the system may lead to devastating neurological conditions. This essay will explore the structure of the limbic system, its functional organization utilizing neurological diseases or damage to demonstrate the association between that specific affected brain region and function.

Neurological disease

2016 ◽  
Author(s):  
James Griffiths ◽  
Kate Drummond
Keyword(s):  
Central Nervous System ◽  
Neurological Disease ◽  
Maternal Morbidity ◽  
Neurological Diseases ◽  
Well Being ◽  
Maternal Deaths ◽  
Obstetric Anaesthesia ◽  
Maternal Morbidity And Mortality ◽  
The Central Nervous System ◽  
Neurological Conditions

This chapter predominantly focuses on the provision of obstetric anaesthesia and analgesia for the parturient with neurological disease. Diseases of the central nervous system are an important cause of maternal morbidity and mortality. Maternal deaths may occur from such conditions as subarachnoid haemorrhage, intracerebral haemorrhage, thrombosis, and epilepsy. Neurological disease may impact on maternal well-being during pregnancy and pregnancy has the potential to exacerbate many neurological diseases. Many neurological conditions also have important implications for the safe conduct of neuraxial anaesthesia and analgesia, such as spina bifida and hydrocephalus. Management of these conditions may require care to be coordinated by a multidisciplinary team including the obstetrician, neurologist, neurosurgeon, and anaesthetist.

Central Nervous System Disorders Associated To Immune Checkpoint Inhibitors

2021 ◽  
Vol 17 ◽  
Author(s):  
Felipe Fanine de Souza ◽  
Julia Petry Trevisani ◽  
Letícia Caroline Breis ◽  
Luís Gustavo Marcelino Sizenando ◽  
Marco Antônio Machado Schlindwein ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Neurological Diseases ◽  
Cns Disorders ◽  
Central Nervous System Disorders ◽  
Wide Range ◽  
The Central Nervous System

: New therapies and alternatives for the containment of tumor progression are being proposed for the treatment of cancer. In this context, monoclonal therapies using immune checkpoint inhibitors (ICI) come as a therapeutic proposal. They are responsible for immunological control by blocking PD-1, PD-L1 and CTLA-4 molecules. However, among the effects caused by therapy, the use of medications is associated with neurological diseases reported as an adverse effect, affecting the central nervous system (CNS) and causing a wide range of symptoms. In this regard, the present bibliographic review presents the main CNS disorders associated with this therapy, in addition to the incidence, symptoms and treatment of these diseases.

scholarly journals Therapeutic Potential of Diosgenin and Its Major Derivatives against Neurological Diseases: Recent Advances

2020 ◽  
Vol 2020 ◽  
pp. 1-16 ◽  
Author(s):  
Bangrong Cai ◽  
Ying Zhang ◽  
Zengtao Wang ◽  
Dujuan Xu ◽  
Yongyan Jia ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Therapeutic Efficacy ◽  
Therapeutic Potential ◽  
Neurological Diseases ◽  
Therapeutic Agents ◽  
Present Review ◽  
Recent Advances ◽  
Wide Range ◽  
The Central Nervous System

Diosgenin (DG), a well-known steroidal sapogenin, is present abundantly in medicinal herbs such as Dioscorea rhizome, Dioscorea villosa, Trigonella foenum-graecum, Smilax China, and Rhizoma polgonati. DG is utilized as a major starting material for the production of steroidal drugs in the pharmaceutical industry. Due to its wide range of pharmacological activities and medicinal properties, it has been used in the treatment of cancers, hyperlipidemia, inflammation, and infections. Numerous studies have reported that DG is useful in the prevention and treatment of neurological diseases. Its therapeutic mechanisms are based on the mediation of different signaling pathways, and targeting these pathways might lead to the development of effective therapeutic agents for neurological diseases. The present review mainly summarizes recent progress using DG and its derivatives as therapeutic agents for multiple neurological disorders along with their various mechanisms in the central nervous system. In particular, those related to therapeutic efficacy for Parkinson’s disease, Alzheimer’s disease, brain injury, neuroinflammation, and ischemia are discussed. This review article also critically evaluates existing limitations associated with the solubility and bioavailability of DG and discusses imperatives for translational clinical research. It briefly recapitulates recent advances in structural modification and novel formulations to increase the therapeutic efficacy and brain levels of DG. In the present review, databases of PubMed, Web of Science, and Scopus were used for studies of DG and its derivatives in the treatment of central nervous system diseases published in English until December 10, 2019. Three independent researchers examined articles for eligibility. A total of 150 articles were screened from the above scientific literature databases. Finally, a total of 46 articles were extracted and included in this review. Keywords related to glioma, ischemia, memory, aging, cognitive impairment, Alzheimer, Parkinson, and neurodegenerative disorders were searched in the databases based on DG and its derivatives.

scholarly journals The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration

2020 ◽  
Author(s):  
Paymaan Jafar-nejad ◽  
Berit Powers ◽  
Armand Soriano ◽  
Hien Zhao ◽  
Daniel A. Norris ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Muscular Atrophy ◽  
Neurological Diseases ◽  
Cell Types ◽  
Rnase H ◽  
Central Administration ◽  
Spinal Motor Neurons ◽  
New Class ◽  
Wide Range ◽  
Therapeutic Development

ABSTRACTAntisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing the field to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal, and non-neuronal cells. Therefore, it is critically important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and robust activity throughout the CNS in neurons, oligodendrocytes, astrocytes, and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.

Neurological consultations and diagnoses in a large, dedicated COVID-19 university hospital

2020 ◽  
Vol 78 (8) ◽  
pp. 494-500 ◽  
Author(s):  
Adalberto STUDART-NETO ◽  
Bruno Fukelmann GUEDES ◽  
Raphael de Luca e TUMA ◽  
Antonio Edvan CAMELO FILHO ◽  
Gabriel Taricani KUBOTA ◽  
...  
Keyword(s):  
Neurological Diseases ◽  
Neuromuscular Disorders ◽  
Neurological Symptoms ◽  
University Hospital ◽  
Special Treatment ◽  
Nasal Swabs ◽  
Neurological Exam ◽  
Neurological Conditions ◽  
De Medicina

ABSTRACT Background: More than one-third of COVID-19 patients present neurological symptoms ranging from anosmia to stroke and encephalopathy. Furthermore, pre-existing neurological conditions may require special treatment and may be associated with worse outcomes. Notwithstanding, the role of neurologists in COVID-19 is probably underrecognized. Objective: The aim of this study was to report the reasons for requesting neurological consultations by internists and intensivists in a COVID-19-dedicated hospital. Methods: This retrospective study was carried out at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil, a 900-bed COVID-19 dedicated center (including 300 intensive care unit beds). COVID-19 diagnosis was confirmed by SARS-CoV-2-RT-PCR in nasal swabs. All inpatient neurology consultations between March 23rd and May 23rd, 2020 were analyzed. Neurologists performed the neurological exam, assessed all available data to diagnose the neurological condition, and requested additional tests deemed necessary. Difficult diagnoses were established in consensus meetings. After diagnosis, neurologists were involved in the treatment. Results: Neurological consultations were requested for 89 out of 1,208 (7.4%) inpatient COVID admissions during that period. Main neurological diagnoses included: encephalopathy (44.4%), stroke (16.7%), previous neurological diseases (9.0%), seizures (9.0%), neuromuscular disorders (5.6%), other acute brain lesions (3.4%), and other mild nonspecific symptoms (11.2%). Conclusions: Most neurological consultations in a COVID-19-dedicated hospital were requested for severe conditions that could have an impact on the outcome. First-line doctors should be able to recognize neurological symptoms; neurologists are important members of the medical team in COVID-19 hospital care.

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