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Clinical Potential of Neurosteroids for CNS Disorders.

ABSTRACT: Neurosteroids are key endogenous molecules in the brain that affect many neural functions. We describe here recent advances in US National Institutes of Health (NIH)-sponsored and other clinical studies of neurosteroids for CNS disorders. The neuronal GABA-A receptor chloride channel is one of the prime molecular targets of neurosteroids. Allopregnanolone-like neurosteroids are potent allosteric agonists as well as direct activators of both synaptic and extrasynaptic GABA-A receptors. Hence, neurosteroids can maximally enhance synaptic phasic and extrasynaptic tonic inhibition. The resulting chloride current conductance generates a form of shunting inhibition that controls network excitability, seizures, and behavior. Such mechanisms of neurosteroids are providing innovative therapies for epilepsy, status epilepticus (SE), traumatic brain injury (TBI), fragile X syndrome (FXS), and chemical neurotoxicity. The neurosteroid field has entered a new era, and many compounds have reached advanced clinical trials. Synthetic analogs have several advantages over natural neurosteroids for clinical use because of their superior bioavailability and safety trends.

SUBMITTER: Reddy DS

PROVIDER: S-EPMC5310676 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Clinical Potential of Neurosteroids for CNS Disorders.

Reddy Doodipala Samba DS Estes William A WA

Trends in pharmacological sciences 20160505 7

Neurosteroids are key endogenous molecules in the brain that affect many neural functions. We describe here recent advances in US National Institutes of Health (NIH)-sponsored and other clinical studies of neurosteroids for CNS disorders. The neuronal GABA-A receptor chloride channel is one of the prime molecular targets of neurosteroids. Allopregnanolone-like neurosteroids are potent allosteric agonists as well as direct activators of both synaptic and extrasynaptic GABA-A receptors. Hence, neu ...[more]

PMID: 27156439

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Project description:Current laboratory testing of cerebrospinal fluid (CSF) does not consistently discriminate between different central nervous system (CNS) disease states. Rapidly distinguishing CNS infections from other brain and spinal cord disorders that share a similar clinical presentation is critical. New approaches focusing on aspects of disease biology, such as immune response profiles that can have stimulus-specific attributes, may be helpful. We undertook this preliminary proof-of-concept study using multiplex ELISA to measure CSF cytokine levels in various CNS disorders (infections, autoimmune/demyelinating diseases, lymphomas, and gliomas) to determine the potential utility of cytokine patterns in differentiating CNS infections from other CNS diseases. Both agglomerative hierarchical clustering and mixture discriminant analyses revealed grouping of CNS disease types based on cytokine expression. To further investigate the ability of CSF cytokine levels to distinguish various CNS disease states, non-parametric statistical analysis was performed. Mann-Whitney test analysis demonstrated that CNS infections are characterized by significantly higher CSF lP-10/CXCL10 levels than the pooled non-infectious CNS disorders (p = 0.0001). Within the infection group, elevated levels of MDC/CCL22 distinguished non-viral from viral infections (p = 0.0048). Each disease group of the non-infectious CNS disorders independently showed IP-10/CXCL10 levels that are significantly lower than the infection group [(autoimmune /demyelinating disorders (p = 0.0005), lymphomas (p = 0.0487), gliomas (p = 0.0294), and controls (p = 0.0001)]. Additionally, of the non-infectious diseases, gliomas can be distinguished from lymphomas by higher levels of GRO/CXCL1 (p = 0.0476), IL-7 (p = 0.0119), and IL-8 (p = 0.0460). Gliomas can also be distinguished from autoimmune/demyelinating disorders by higher levels of GRO/CXCL1 (p = 0.0044), IL-7 (p = 0.0035) and IL-8 (p = 0.0176). Elevated CSF levels of PDGF-AA distinguish lymphomas from autoimmune/demyelinating cases (p = 0.0130). Interrogation of the above comparisons using receiver operator characteristic analysis demonstrated area under the curve (AUC) values (ranging from 0.8636-1.0) that signify good to excellent utility as potential diagnostic discriminators. In conclusion, our work indicates that upon formal validation, measurement of CSF cytokine levels may have clinical utility in both identifying a CNS disorder as infectious in etiology and, furthermore, in distinguishing viral from non-viral CNS infections.

Project description:Objective: To analyze the positive and recurrence rates of different autoantibody-associated demyelination disorders in children in Southwest China, and describe the clinical, radiological, and prognostic features of the myelin oligodendrocyte glycoprotein antibody (MOG-ab) and aquaporin-4 antibody (AQP4-ab) associated disease. This study also summarizes steroid maintenance therapy approaches for MOG-ab-positive children. Methods: A total of 160 children presenting with acquired demyelinating syndromes (ADS) between January 2016 and December 2019 were tested for MOG-ab and AQP4-ab. Clinical data, MRI scans, and survival analyses were compared between MOG-ab-positive and AQP4-ab-positive children. Evolution of serologic status and treatment response to immunosuppressants were collected in MOG-ab-positive children. Results: Of the 160 included children, the MOG-ab positivity rate (47.4%) was significantly higher than the AQP4-ab (5%) positivity rate. The recurrence rate for AQP4-ab disease (71.4%) was higher than that of MOG-ab disease (30.1%). For 135 children with both MOG-ab and AQP4-ab tested, the median age at onset was 7 (interquartile range [IQR] 5-10) years, and the median follow-up period was 19 (IQR 13-27.5) months. MOG-ab-positive children more frequently presented with acute disseminated encephalomyelitis, had deep gray matter lesions on MRI, had a better clinical and radiological recovery, and were less likely to have sustained disability than AQP4-ab-positive children. In MOG-ab-positive and AQP4-ab-positive children, maintenance therapy was a protective factor for recurrence, but presenting optic neuritis was a predictor of earlier relapse. A high Expanded Disability Status Scale score at onset was associated with sustained disability. Steroid maintenance therapy longer than 6 months after the initial attack was associated with a lower risk of a second relapse in MOG-ab-positive children. On serial serum MOG antibody analysis, clinical relapse occurred in 34.6% of children with persistent seropositivity, but none of the children who converted to seronegative status experienced relapse. Conclusion: The MOG antibody is more common in children with ADS than the AQP4 antibody. MOG-ab-positive children are characterized by distinct clinical and radiological features. Although some MOG-ab-positive children experience relapsing courses or have persistently seropositive status, they still predict a better outcome than AQP4-ab-positive children.

Dataset Information

Clinical Potential of Neurosteroids for CNS Disorders.

Publications

Clinical Potential of Neurosteroids for CNS Disorders.

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