Neuroinflammation mediated by microglia and oxidative stress play pivotal roles in the development of chronic temporal lobe epilepsy(TLE).We postulated that kainic acid(KA)-Induced status epilepticus triggers microgli...Neuroinflammation mediated by microglia and oxidative stress play pivotal roles in the development of chronic temporal lobe epilepsy(TLE).We postulated that kainic acid(KA)-Induced status epilepticus triggers microglia-dependent inflammation,leading to neuronal damage,a lowered seizure threshold,and the emergence of spontaneous recurrent seizures(SRS).Extensive evidence from our laboratory suggests that dextromethorphan(DM),even in ultra-low doses,has anti-inflammatory and neuroprotective effects in many animal models of neurodegenerative disease.Our results showed that administration of DM(10 ng/kg per day;subcutaneously via osmotic minipump for 4 weeks)significantly mitigated the residual effects of KA,including the frequency of SRS and seizure susceptibility.In addition,DM-treated rats showed improved cognitive function and reduced hippocampal neuronal loss.We found suppressed microglial activation-mediated neuroinflammation and decreased expression of hippocampal gp91^(phox) and p47^(phox) proteins in KA-induced chronic TLE rats.Notably,even after discontinuation of DM treatment,ultra-low doses of DM continued to confer long-term anti-seizure and neuroprotective effects,which were attributed to the inhibition of microglial NADPH oxidase 2 as revealed by mechanistic studies.展开更多
Neurodegenerative disorders including Alzheimer＇s disease are characterized by chronic in- flammation in the central nervous system. The two main glial types involved in inflammatory reactions are microglia and astro...Neurodegenerative disorders including Alzheimer＇s disease are characterized by chronic in- flammation in the central nervous system. The two main glial types involved in inflammatory reactions are microglia and astrocytes. While these cells normally protect neurons by providing nutrients and growth factors, disease specific stimuli can induce glial secretion of neurotoxins. It has been hypothesized that reducing glia-mediated inflammation could diminish neuronal loss. This hypothesis is supported by observations that chronic use of non-steroidal anti-inflamma- tory drugs （NSAIDs） is linked with lower incidences of neurodegenerative disease. It is possible that the NSAIDs are not potent enough to appreciably reduce chronic neuroinflammation after disease processes are fully established. Gold thiol compounds, including auranofin, comprise an- other class of medications effective at reducing peripheral inflammation. We have demonstrated that auranofin inhibits human microglia- and astrocyte-mediated neurotoxicity. Other drugs which are currently used to treat peripheral inflammatory conditions could be helpful in neu- rodegenerative disease. Three different classes of anti-inflammatory compounds, which have a potential to inhibit neuroinflammation are highlighted below.展开更多
BACKGROUND Dextromethorphan is a prevalent antitussive agent that can be easily obtained as an over-the-counter medication.There has been a growing number of reported cases of toxicity in recent years.Generally,there ...BACKGROUND Dextromethorphan is a prevalent antitussive agent that can be easily obtained as an over-the-counter medication.There has been a growing number of reported cases of toxicity in recent years.Generally,there are numerous instances of mild symptoms,with only a limited number of reports of severe cases necessitating intensive care.We presented the case of a female who ingested 111 tablets of dextromethorphan,leading to shock and convulsions and requiring intensive care that ultimately saved her life.CASE SUMMARY A 19-year-old female was admitted to our hospital via ambulance,having overdosed on 111 tablets of dextromethorphan(15 mg)obtained through an online importer in a suicide attempt.The patient had a history of drug abuse and multiple self-inflicted injuries.At the time of admission,she exhibited symptoms of shock and altered consciousness.However,upon arrival at the hospital,the patient experienced recurrent generalized clonic convulsions and status epilepticus,necessitating tracheal intubation.The convulsions were determined to have been caused by decreased cerebral perfusion pressure secondary to shock,and noradrenaline was administered as a vasopressor.Gastric lavage and activated charcoal were also administered after intubation.Through systemic management in the intensive care unit,the patient’s condition stabilized,and the need for vasopressors ceased.The patient regained consciousness and was extubated.The patient was subsequently transferred to a psychiatric facility,as suicidal ideation persisted.CONCLUSION We report the first case of shock caused by an overdose of dextromethorphan.展开更多
Behavioral and psychological symptoms including agitation are common in dementia,and are associated with decreased quality of life,increased risk of institutionalization,and greater patient and caregiver distress.Phar...Behavioral and psychological symptoms including agitation are common in dementia,and are associated with decreased quality of life,increased risk of institutionalization,and greater patient and caregiver distress.Pharmacological agents used for management of behavioral and psychological symptoms of dementia are limited by their tolerability,prompting a need for identifying efficacious and safe pharmacological treatments for managing agitation in dementia.The combination of dextromethorphan and quinidine sulfate is approved for pseudobulbar affect,and may be effective in managing agitation in dementia.A review of literature found only one randomized controlled trial that evaluated the use of dextromethorphan-quinidine for the management of agitation in dementia when compared to placebo.Data from this trial demonstrated that dextromethorphan-quinidine decreased agitation in dementia,and was well tolerated.Although promising,further research is needed before dextromethorphan-quinidine combination can be accepted as a standard treatment for agitation in dementia.展开更多
基金supported by the National Major Scientific and Technological Special Project for Significant New Drugs Development(2019zx09301102)the Project of Liaoning Provincial Department of Education(LJKZ0826)the Open Project of National and Local Joint Engineering Research Center for Drug Research and Development of Neurodegenerative Diseases(2022GCYJZX-YB02).
文摘Neuroinflammation mediated by microglia and oxidative stress play pivotal roles in the development of chronic temporal lobe epilepsy(TLE).We postulated that kainic acid(KA)-Induced status epilepticus triggers microglia-dependent inflammation,leading to neuronal damage,a lowered seizure threshold,and the emergence of spontaneous recurrent seizures(SRS).Extensive evidence from our laboratory suggests that dextromethorphan(DM),even in ultra-low doses,has anti-inflammatory and neuroprotective effects in many animal models of neurodegenerative disease.Our results showed that administration of DM(10 ng/kg per day;subcutaneously via osmotic minipump for 4 weeks)significantly mitigated the residual effects of KA,including the frequency of SRS and seizure susceptibility.In addition,DM-treated rats showed improved cognitive function and reduced hippocampal neuronal loss.We found suppressed microglial activation-mediated neuroinflammation and decreased expression of hippocampal gp91^(phox) and p47^(phox) proteins in KA-induced chronic TLE rats.Notably,even after discontinuation of DM treatment,ultra-low doses of DM continued to confer long-term anti-seizure and neuroprotective effects,which were attributed to the inhibition of microglial NADPH oxidase 2 as revealed by mechanistic studies.
基金supported by a grant from the Jack BrownFamily Alzheimer’s Disease Research Foundation
文摘Neurodegenerative disorders including Alzheimer＇s disease are characterized by chronic in- flammation in the central nervous system. The two main glial types involved in inflammatory reactions are microglia and astrocytes. While these cells normally protect neurons by providing nutrients and growth factors, disease specific stimuli can induce glial secretion of neurotoxins. It has been hypothesized that reducing glia-mediated inflammation could diminish neuronal loss. This hypothesis is supported by observations that chronic use of non-steroidal anti-inflamma- tory drugs （NSAIDs） is linked with lower incidences of neurodegenerative disease. It is possible that the NSAIDs are not potent enough to appreciably reduce chronic neuroinflammation after disease processes are fully established. Gold thiol compounds, including auranofin, comprise an- other class of medications effective at reducing peripheral inflammation. We have demonstrated that auranofin inhibits human microglia- and astrocyte-mediated neurotoxicity. Other drugs which are currently used to treat peripheral inflammatory conditions could be helpful in neu- rodegenerative disease. Three different classes of anti-inflammatory compounds, which have a potential to inhibit neuroinflammation are highlighted below.
文摘BACKGROUND Dextromethorphan is a prevalent antitussive agent that can be easily obtained as an over-the-counter medication.There has been a growing number of reported cases of toxicity in recent years.Generally,there are numerous instances of mild symptoms,with only a limited number of reports of severe cases necessitating intensive care.We presented the case of a female who ingested 111 tablets of dextromethorphan,leading to shock and convulsions and requiring intensive care that ultimately saved her life.CASE SUMMARY A 19-year-old female was admitted to our hospital via ambulance,having overdosed on 111 tablets of dextromethorphan(15 mg)obtained through an online importer in a suicide attempt.The patient had a history of drug abuse and multiple self-inflicted injuries.At the time of admission,she exhibited symptoms of shock and altered consciousness.However,upon arrival at the hospital,the patient experienced recurrent generalized clonic convulsions and status epilepticus,necessitating tracheal intubation.The convulsions were determined to have been caused by decreased cerebral perfusion pressure secondary to shock,and noradrenaline was administered as a vasopressor.Gastric lavage and activated charcoal were also administered after intubation.Through systemic management in the intensive care unit,the patient’s condition stabilized,and the need for vasopressors ceased.The patient regained consciousness and was extubated.The patient was subsequently transferred to a psychiatric facility,as suicidal ideation persisted.CONCLUSION We report the first case of shock caused by an overdose of dextromethorphan.
文摘Behavioral and psychological symptoms including agitation are common in dementia,and are associated with decreased quality of life,increased risk of institutionalization,and greater patient and caregiver distress.Pharmacological agents used for management of behavioral and psychological symptoms of dementia are limited by their tolerability,prompting a need for identifying efficacious and safe pharmacological treatments for managing agitation in dementia.The combination of dextromethorphan and quinidine sulfate is approved for pseudobulbar affect,and may be effective in managing agitation in dementia.A review of literature found only one randomized controlled trial that evaluated the use of dextromethorphan-quinidine for the management of agitation in dementia when compared to placebo.Data from this trial demonstrated that dextromethorphan-quinidine decreased agitation in dementia,and was well tolerated.Although promising,further research is needed before dextromethorphan-quinidine combination can be accepted as a standard treatment for agitation in dementia.
