scholarly journals Neuroactive steroids, their metabolites, and neuroinflammation

2012 ◽  
Vol 49 (3) ◽  
pp. R125-R134 ◽  
Author(s):  
Silvia Giatti ◽  
Mariaserena Boraso ◽  
Roberto Cosimo Melcangi ◽  
Barbara Viviani
Keyword(s):  
Nervous System ◽  
Biomedical Research ◽  
Experimental Models ◽  
Neuroactive Steroids ◽  
Steroid Metabolism ◽  
Neuroactive Steroid ◽  
Neuroprotective Strategy ◽  
Testosterone Metabolites ◽  
Inflammatory Effect

Neuroinflammation represents a common feature of many neurodegenerative diseases implicated both in their onset and progression. Neuroactive steroids act as physiological regulators and protective agents in the nervous system. Therefore, the attention of biomedical research has been recently addressed in evaluating whether neuroactive steroids, such as progestagens, androgens, and estrogens may also affect neuroinflammatory pathways. Observations so far obtained suggest a general anti-inflammatory effect with a beneficial relapse on several neurodegenerative experimental models, thus confirming the potentiality of a neuroprotective strategy based on neuroactive steroids. In this scenario, neuroactive steroid metabolism and the sophisticated machinery involved in their signaling are becoming especially attractive. In particular, because metabolism of neuroactive steroids as well as expression of their receptors is affected during the course of neurodegenerative events, a crucial role of progesterone and testosterone metabolites in modulating neuroinflammation and neurodegeneration may be proposed. In the present review, we will address this issue, providing evidence supporting the hypothesis that the efficacy of neuroactive steroids could be improved through the use of their metabolites.

scholarly journals Physiopathological Role of Neuroactive Steroids in the Peripheral Nervous System

2020 ◽  
Vol 21 (23) ◽  
pp. 9000
Author(s):  
Eva Falvo ◽  
Silvia Diviccaro ◽  
Roberto Cosimo Melcangi ◽  
Silvia Giatti
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Experimental Models ◽  
Neuroactive Steroids ◽  
Physiological Status ◽  
Sexually Dimorphic ◽  
Protective Effects ◽  
Traumatic Injuries ◽  
High Prevalence

Peripheral neuropathy (PN) refers to many conditions involving damage to the peripheral nervous system (PNS). Usually, PN causes weakness, numbness and pain and is the result of traumatic injuries, infections, metabolic problems, inherited causes, or exposure to chemicals. Despite the high prevalence of PN, available treatments are still unsatisfactory. Neuroactive steroids (i.e., steroid hormones synthesized by peripheral glands as well as steroids directly synthesized in the nervous system) represent important physiological regulators of PNS functionality. Data obtained so far and here discussed, indeed show that in several experimental models of PN the levels of neuroactive steroids are affected by the pathology and that treatment with these molecules is able to exert protective effects on several PN features, including neuropathic pain. Of note, the observations that neuroactive steroid levels are sexually dimorphic not only in physiological status but also in PN, associated with the finding that PN show sex dimorphic manifestations, may suggest the possibility of a sex specific therapy based on neuroactive steroids.

scholarly journals Peripheral Mechanisms of Symptom Generation in Irritable Bowel Syndrome

2001 ◽  
Vol 15 (suppl b) ◽  
pp. 14B-16B ◽  
Author(s):  
Stephen M Collins
Keyword(s):  
Nervous System ◽  
Irritable Bowel Syndrome ◽  
Experimental Models ◽  
Low Grade ◽  
Sensory Physiology ◽  
Somatic Pain ◽  
Inflammatory Stimuli ◽  
The Central Nervous System ◽  
Irritable Bowel

There is considerable interest in the mechanisms that underlie symptom generation in irritable bowel syndrome (IBS) and particularly those mechanisms peripheral to higher centres in the nervous system. While the central nervous system is important in IBS, it is restricted largely to the role of behaviour in stress perception and symptom reporting. The gut and the autonomic nervous system are principal areas of research in identifying mechanisms underlying symptom generation and in the identification of new targets for drug development. While motility changes occur in IBS, they are neither specific nor predictable, and this is one reason why drugs aimed at influencing motility patterns have enjoyed limited success to date. This success has prompted interest in sensory physiology to explain pain and other discomforts expressed by patients with IBS. Patients with IBS exhibit intolerance to rectal distension and other manoeuvres of the gut, while exhibiting normal or raised thresholds for somatic pain. The mechanisms underlying the development of hyperalgesia or allodynia in the gut remain to be determined. In other systems and experimental models, low grade inflammation is a predicable inducer of these states, and recent evidence suggests that a subpopulation of patients with IBS develop chronic symptoms after acute gastroenteritis. This and other inflammatory stimuli may induce a hyperalgesic state and alter motor function in patients with IBS. Substances that mediate these changes are not fully understood, but there is growing recognition of the role of serotonin as a sensitizing agent.

scholarly journals α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response

2021 ◽  
Author(s):  
Alberto Delaidelli ◽  
Mette Richner ◽  
Lixiang Jiang ◽  
Amelia van der Laan ◽  
Ida Bergholdt Jul Christiansen ◽  
...  
Keyword(s):  
Nervous System ◽  
Parkinson Disease ◽  
Redox Homeostasis ◽  
Alpha Synuclein ◽  
Experimental Models ◽  
Motor Nucleus ◽  
Related Factor ◽  
Dorsal Motor Nucleus ◽  
Anti Oxidant

Circumstantial evidence points to a pathological role of alpha-synuclein (aSyn; gene symbol SNCA), conferred by aSyn misfolding and aggregation, in Parkinson disease (PD) and related synucleionpathies. Several findings in experimental models implicate perturbations in the tissue homeostatic mechanisms triggered by pathological aSyn accumulation, including impaired redox homeostasis, as significant contributors in the pathogenesis of PD. The nuclear factor erythroid 2-related factor (NRF2) is recognized as the master regulator of cellular anti-oxidant response, both under physiological as well as in pathological conditions. Using immunohistochemical analyses, we show a robust nuclear NRF2 accumulation in post-mortem PD midbrain, detected by NRF2 phosphorylation on serine residue 40 (nuclear active p-NRF2, S40). Curated gene expression analyses of four independent publicly available microarray datasets revealed considerable alterations in NRF2-responsive genes in the disease affected regions in PD, including substantia nigra, dorsal motor nucleus of vagus, locus coeruleus and globus pallidus. To further examine the putative role of pathological aSyn accumulation on nuclear NRF2 response, we employed a transgenic mouse model of synucleionopathy (M83 line, Prnp-SNCA*Ala53Thr), which manifest widespread aSyn pathology (phosphorylated aSyn; S129) in the nervous system following intramuscular inoculation of exogenous fibrillar aSyn. We observed strong immunodetection of nuclear NRF2 in neuronal populations harboring p-aSyn (S129), and found an aberrant anti-oxidant and inflammatory gene response in the affected neuraxis. Taken together, our data support the notion that pathological aSyn accumulation impairs the redox homeostasis in nervous system, and boosting neuronal anti-oxidant response is potentially a promising approach to mitigate neurodegeneration in PD and related diseases.

scholarly journals The role of prolactin in central nervous system inflammation

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Edgar Ramos-Martinez ◽  
Ivan Ramos-Martínez ◽  
Gladys Molina-Salinas ◽  
Wendy A. Zepeda-Ruiz ◽  
Marco Cerbon
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neuronal Damage ◽  
Neurological Diseases ◽  
Neuroprotective Effect ◽  
General Information ◽  
Experimental Models ◽  
Neuroprotective Effects ◽  
Anti Inflammatory

Abstract Prolactin has been shown to favor both the activation and suppression of the microglia and astrocytes, as well as the release of inflammatory and anti-inflammatory cytokines. Prolactin has also been associated with neuronal damage in diseases such as multiple sclerosis, epilepsy, and in experimental models of these diseases. However, studies show that prolactin has neuroprotective effects in conditions of neuronal damage and inflammation and may be used as neuroprotector factor. In this review, we first discuss general information about prolactin, then we summarize recent findings of prolactin function in inflammatory and anti-inflammatory processes and factors involved in the possible dual role of prolactin are described. Finally, we review the function of prolactin specifically in the central nervous system and how it promotes a neuroprotective effect, or that of neuronal damage, particularly in experimental autoimmune encephalomyelitis and during excitotoxicity. The overall studies indicated that prolactin may be a promising molecule for the treatment of some neurological diseases.

scholarly journals Experimental Study on the Role of 5-Ht2 Serotonin Receptors in the Mechanism of Anti-Inflammatory and Antihyperalgesic Action of Antidepressant Fluoxetine

Folia Medica ◽  
2014 ◽  
Vol 56 (1) ◽  
pp. 43-49 ◽  
Author(s):  
Ilia D. Kostadinov ◽  
Delian P. Delev ◽  
Marianna A. Murdjeva ◽  
Ivanka I. Kostadinova
Keyword(s):  
Repeated Administration ◽  
Experimental Models ◽  
Prolonged Treatment ◽  
Saline Control ◽  
Intraplantar Injection ◽  
Mechanical Pressure ◽  
Anti Inflammatory ◽  
Single And Repeated Administration ◽  
Inflammatory Effect

ABSTRACT INTRODUCTION: Fluoxetine is an antidepressant that has anti-inflammatory and antihyperalgesic effects in experimental models of pain and inflammation. The AIM of the present study was to determine the role of 5-HT2 receptors in the mechanism of anti-inflammatory and antihyperalgesic action of fluoxetine after single and repeated administration of the drug. MATERIALS AND METHODS: 40 male Wistar rats were randomly divided in five groups (n = 8) treated for 14 days with saline (control), diclofenac (positive control), fluoxetine, cyproheptadine (5-HT2 antagonist), and fluoxetine + cyproheptadine, respectively. We used the experimental model of inflammation induced by intraplantar injection of carrageenan and nociceptive test with mechanical pressure on the inflamed hind paw. RESULTS: Single and repeated administration of fluoxetine showed that it had significant anti-inflammatory and antihyperalgesic effects when compared with the control (p < 0.05). Cyproheptadine did not change significantly the anti-inflammatory effect of fluoxetine in the first 4 hours, after a single administration. At 24 hours the combination did not differ statistically when compared with the control. Cyproheptadin did not change significantly the anti-inflammatory effect of fluoxetine after repeated administration. After prolonged treatment the group that received fluoxetine + cyproheptadine showed a statistically significant increase in paw pressure to withdraw the hind paw compared with that treated with fluoxetine alone (p < 0.05). CONCLUSIONS: Fluoxetine has anti-inflammatory and antihyperalgesic effects in the carrageenan model of inflammation. 5-HT2 receptor mediated its anti-inflammatory effect in single dose treated animals. Spinal 5-HT2 receptors are involved in the antihyperalgesic effect of fluoxetine after repeated administration

scholarly journals Role of Neuroactive Steroids in the Peripheral Nervous System

2011 ◽  
Vol 2 ◽  
Author(s):  
Roberto Cosimo Melcangi ◽  
Silvia Giatti ◽  
Marzia Pesaresi ◽  
Donato Calabrese ◽  
Nico Mitro ◽  
...  
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Neuroactive Steroids

scholarly journals α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Alberto Delaidelli ◽  
Mette Richner ◽  
Lixiang Jiang ◽  
Amelia van der Laan ◽  
Ida Bergholdt Jul Christiansen ◽  
...  
Keyword(s):  
Nervous System ◽  
Parkinson Disease ◽  
Redox Homeostasis ◽  
Alpha Synuclein ◽  
Experimental Models ◽  
Motor Nucleus ◽  
Related Factor ◽  
Dorsal Motor Nucleus ◽  
Anti Oxidant

AbstractCircumstantial evidence points to a pathological role of alpha-synuclein (aSyn; gene symbol SNCA), conferred by aSyn misfolding and aggregation, in Parkinson disease (PD) and related synucleinopathies. Several findings in experimental models implicate perturbations in the tissue homeostatic mechanisms triggered by pathological aSyn accumulation, including impaired redox homeostasis, as significant contributors in the pathogenesis of PD. The nuclear factor erythroid 2-related factor (NRF2/Nrf2) is recognized as ‘the master regulator of cellular anti-oxidant response’, both under physiological as well as in pathological conditions. Using immunohistochemical analyses, we show a robust nuclear NRF2 accumulation in post-mortem PD midbrain, detected by NRF2 phosphorylation on the serine residue 40 (nuclear active p-NRF2, S40). Curated gene expression analyses of four independent publicly available microarray datasets revealed considerable alterations in NRF2-responsive genes in the disease affected regions in PD, including substantia nigra, dorsal motor nucleus of vagus, locus coeruleus and globus pallidus. To further examine the putative role of pathological aSyn accumulation on nuclear NRF2 response, we employed a transgenic mouse model of synucleionopathy (M83 line, expressing the mutant human A53T aSyn), which manifests widespread aSyn pathology (phosphorylated aSyn; S129) in the nervous system following intramuscular inoculation of exogenous fibrillar aSyn. We observed strong immunodetection of nuclear NRF2 in neuronal populations harboring p-aSyn (S129), and found an aberrant anti-oxidant and inflammatory gene response in the affected neuraxis. Taken together, our data support the notion that pathological aSyn accumulation impairs the redox homeostasis in nervous system, and boosting neuronal anti-oxidant response is potentially a promising approach to mitigate neurodegeneration in PD and related diseases.

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