RESUMO
BACKGROUND: Coronavirus disease 19 (COVID-19) is the disease caused by SARS-CoV-2, a highly infectious member of the coronavirus family, which emerged in December 2019 in "Wuhan, China". It induces respiratory illness ranging from mild symptoms to severe disease. It was declared a "pandemic" by the World Health Organization (WHO) in March 2020. Since then, a vast number of clinical and experimental studies have been conducted to identify effective approaches for its prevention and treatment. MAIN BODY: The pathophysiology of COVID-19 represents an unprecedented challenge; it triggers a strong immune response, which may be exacerbated by "a cytokine storm syndrome". It also induces thrombogenesis and may trigger multi-organ injury. Therefore, different drug classes have been proposed for its treatment and prevention, such as antivirals, anti-SARS-CoV-2 antibody agents (monoclonal antibodies, convalescent plasma, and immunoglobulins), anti-inflammatory drugs, immunomodulators, and anticoagulant drugs. To the best of our knowledge, this review is the first to present, discuss, and summarize the current knowledge about the different drug classes used for the treatment of COVID-19, with special emphasis on their targets, mechanisms of action, and important adverse effects and drug interactions. Additionally, we spotlight the latest "October 2023" important guidelines (NIH, IDSA, and NICE) and FDA approval or authorization regarding the use of these agents in the management of COVID-19. CONCLUSION: Despite the wide array of therapeutic strategies introduced for the treatment of COVID-19, one of the most prominent therapeutic challenges is SARS-CoV-2 mutations and emerging new variants and subvariants. Currently, the anti-COVID-19 drug pipeline is continuously affording novel treatments to face this growing challenge.
Assuntos
Antivirais , COVID-19 , Humanos , Antivirais/uso terapêutico , Antivirais/farmacologia , SARS-CoV-2 , Anticorpos Antivirais , Anticorpos MonoclonaisRESUMO
Chemotherapy-induced cognitive impairment (CICI) is a general term describing cognitive dysfunction during/after treatment with chemotherapeutic agents. CICI represents a significant medical problem due to its increasing prevalence with the lack of robust therapeutic approaches. This study aimed at investigating the effects of chronic treatment with amisulpride (5 mg/kg/day) in the management of 5-fluorouracil (5-FU)-induced cognitive deficits in Wistar rats. Rats received 5 intraperitoneal injections of 5-FU (25 mg/kg every 3 days). 5-FU treatment induced impairments in spatial learning (reduction in object location discrimination ratio) and non-spatial learning (reduction in novel object recognition discrimination ratio). Moreover, 5-FU induced a decrease in the activity of the Wnt/GSK-3ß/ß-catenin pathway with a decrease in brain-derived neurotrophic factor (BDNF) level in the hippocampus. These changes were associated with an increase in the expression of the pro-inflammatory cytokines; tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), in hippocampal tissue sections accompanied by a decrease in the number of Ki-67 positive cells (indicating a decrease in proliferative capacity), a decrease in the Nissl's granules optical density (denoting neurodegeneration), a decrease in the number of viable intact neurons with an increase in the expression of ß-amyloid and caspase-3. Amisulpride enhanced Wnt/GSK-3ß/ß-catenin signaling, increased BDNF levels, and abrogated 5-FU-induced neuroinflammation, apoptosis, ß-amyloid accumulation, and neurodegenerative changes with an improvement of cognitive performance. This study draws attention to the pro-cognitive effects of amisulpride in 5-FU-exposed rats that could be attributed to enhancing hippocampal Wnt/GSK-3ß/ß-catenin signaling pathway, and this could offer a promising therapeutic option for subjects with CICI.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Disfunção Cognitiva , Humanos , Ratos , Animais , Ratos Wistar , Glicogênio Sintase Quinase 3 beta/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Amissulprida/farmacologia , Fluoruracila/farmacologia , beta Catenina/metabolismo , Via de Sinalização Wnt , Hipocampo , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , CogniçãoRESUMO
Several reports indicate a plausible role of calcium (Ca2+) permeable AMPA glutamate receptors (with RNA hypo-editing at the GluA2 Q/R site) and the subsequent excitotoxicity-mediated neuronal death in the pathogenesis of a wide array of neurological disorders including autism spectrum disorder (ASD). This study was designed to examine the effects of chronic risperidone treatment on the expression of adenosine deaminase acting on RNA 2 (Adar2), the status of AMPA glutamate receptor GluA2 editing, and its effects on oxidative/nitrosative stress and excitotoxicity-mediated neuronal death in the prenatal valproic acid (VPA) rat model of ASD. Prenatal VPA exposure was associated with autistic-like behaviors accompanied by an increase in the apoptotic marker "caspase-3" and a decrease in the antiapoptotic marker "BCL2" alongside a reduction in the Adar2 relative gene expression and an increase in GluA2 Q:R ratio in the hippocampus and the prefrontal cortex. Risperidone, at doses of 1 and 3 mg, improved the VPA-induced behavioral deficits and enhanced the Adar2 relative gene expression and the subsequent GluA2 subunit editing. This was reflected on the cellular level where risperidone impeded VPA-induced oxidative/nitrosative stress and neurodegenerative changes. In conclusion, the present study confirms a possible role for Adar2 downregulation and the subsequent hypo-editing of the GluA2 subunit in the pathophysiology of the prenatal VPA rat model of autism and highlights the favorable effect of risperidone on reversing the RNA editing machinery deficits, giving insights into a new possible mechanism of risperidone in autism.
Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Animais , Feminino , Gravidez , Ratos , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismo , Transtorno do Espectro Autista/induzido quimicamente , Transtorno Autístico/induzido quimicamente , Transtorno Autístico/tratamento farmacológico , Transtorno Autístico/genética , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Risperidona/farmacologia , RNA/metabolismo , Edição de RNA , Ácido Valproico/efeitos adversosRESUMO
Significant efforts are increasingly directed towards identifying novel therapeutic targets for autism spectrum disorder (ASD) with a rising role of aberrant glutamatergic transmission in the pathogenesis of ASD-associated cellular and behavioral deficits. This study aimed at investigating the role of chronic memantine (20 mg/kg/day) and aripiprazole (3 mg/kg/day) combination therapy in the management of prenatal sodium valproate (VPA)-induced autistic-like/cognitive deficits in male Wistar rats. Pregnant female rats received a single intraperitoneal injection of VPA (600 mg/kg) to induce autistic-like behaviors in their offspring. Prenatal VPA induced autistic-like symptoms (decreased social interaction and the appearance of stereotyped behavior) with deficits in spatial learning (in Morris water maze) and cognitive flexibility (in the attentional set-shifting task) in addition to decreased hippocampal protein levels of phosphorylated cAMP response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and gene expression of glutamate transporter-1 (Glt-1) with a decline in GABA/glutamate ratio (both measured by HPLC). These were accompanied by the appearance of numerous neurofibrillary tangles (NFTs) with enhanced apoptosis in hippocampal sections. Memantine/aripiprazole combination increased the protein levels of p-CREB, BDNF, and Glt-1 gene expression with restoration of GABA/glutamate balance, attenuation of VPA-induced neurodegenerative changes and autistic-like symptoms, and improvement of cognitive performance. This study draws attention to the favorable cognitive effects of memantine/aripiprazole combination in autistic subjects which could be mediated via enhancing CREB/BDNF signaling with increased expression of astrocytic Glt-1 and restoration of GABA/glutamate balance, leading to inhibition of hippocampal NFTs formation and neuronal apoptosis.
Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Disfunção Cognitiva , Animais , Feminino , Masculino , Gravidez , Ratos , Aripiprazol/efeitos adversos , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno Autístico/induzido quimicamente , Transtorno Autístico/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/complicações , Modelos Animais de Doenças , Ácido gama-Aminobutírico/farmacologia , Glutamatos/efeitos adversos , Hipocampo , Homeostase , Memantina/efeitos adversos , Ratos Wistar , Ácido ValproicoRESUMO
Oxidative stress induced neurotoxicity is increasingly perceived as an important neuropathologic mechanism underlying the motor and behavioral phenotypes associated with Huntington's disease (HD). Repeated exposure to 3-nitropropionic acid (3-NP) induces neurotoxic changes which closely simulate the neuropathological and behavioral characteristics of HD. This study aimed at evaluating the prophylactic effects of the dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) inhibitor "harmine" against 3-NP-indued neurotoxicity and HD-like symptoms. The potential prophylactic effect of harmine (10 mg/kg/day; intraperitoneal) was investigated on 3-NP-induced motor and cognitive HD-like deficits, nuclear factor erythroid 2 like 2 (NRF2), AMP kinase (AMPK) and p21 protein levels and the gene expression of haem oxygenase-1 (Ho-1), NAD(P)H: quinone oxidoreductase-1 (Nqo-1) and p62 in addition to redox imbalance and histological neurotoxic changes in the striatum, prefrontal cortex, and hippocampus of male Wistar rats. Harmine successfully increased the protein levels of NRF2, AMPK and p21 and the gene expression of Ho-1, Nqo-1 and p62, restored redox homeostasis, and reduced CASPASE-3 level. This was reflected in attenuation of 3-NP-induced neurodegenerative changes and improvement of rats' motor and cognitive performance. This study draws attention to the protective role of harmine against 3-NP-induced motor and cognitive dysfunction that could be mediated via enhancing NRF2-mediated signaling with subsequent amelioration of oxidative stress injury via NRF2 activators, p21 and AMPK, in the striatum, prefrontal cortex, and hippocampus which could offer a promising therapeutic tool to slow the progression of HD.
Assuntos
Proteínas Quinases Ativadas por AMP , Inibidor de Quinase Dependente de Ciclina p21 , Harmina , Doença de Huntington , Fármacos Neuroprotetores , Síndromes Neurotóxicas , Proteínas Quinases Ativadas por AMP/metabolismo , Adenilato Quinase/metabolismo , Animais , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Harmina/farmacologia , Doença de Huntington/induzido quimicamente , Doença de Huntington/metabolismo , Doença de Huntington/prevenção & controle , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/efeitos adversos , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/prevenção & controle , Nitrocompostos/antagonistas & inibidores , Nitrocompostos/farmacologia , Estresse Oxidativo , Propionatos/antagonistas & inibidores , Propionatos/farmacologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
Tranexamic acid (TXA) is widely utilized to control perioperative bleeding. TXA is considered a safe drug with few serious adverse effects, but many studies report TXA-associated seizures, especially with cardiac surgeries. Usually, TXA-associated seizures persist for a few minutes with no progression into status epilepticus. Here, we report, for the first time, a case of refractory status epilepticus after IV injection of TXA in a paediatric non-cardiac surgery. This case report and literature review aim to increase awareness about TXA-associated seizures and to provide mechanistic-based prevention and treatment recommendations. During adenotonsillectomy for a 4-year-old male child, TXA infusion started after induction of anaesthesia for surgical bleeding prophylaxis. During recovery from anaesthesia, the patient developed tonic-clonic convulsions which did not improve after two IV doses of midazolam but showed an improvement after a dose of propofol. The patient did not regain consciousness and was transferred to the ICU. He had recurrent treatment-resistant attacks of tonic-clonic convulsions. The patient developed acute kidney injury and died after 18 hours. In high-risk patients, using the lowest effective dose with early termination of TXA infusion and prolongation of administration of anaesthetics may prevent seizures. General anaesthetics (propofol and halogenated inhaled anaesthetics) are considered the first line for prevention/treatment of TXA-associated seizures.
Assuntos
Antifibrinolíticos , Propofol , Estado Epiléptico , Ácido Tranexâmico , Antifibrinolíticos/uso terapêutico , Perda Sanguínea Cirúrgica/prevenção & controle , Criança , Pré-Escolar , Humanos , Masculino , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/prevenção & controle , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/complicações , Estado Epiléptico/tratamento farmacológico , Ácido Tranexâmico/uso terapêuticoRESUMO
Low-dose repeated lipopolysaccharide pre-challenge followed by chronic mild stress (LPS/CMS) protocol has been introduced as a rodent model of depression combining the roles of immune activation and chronic psychological stress. However, the impact of this paradigm on cognitive functioning has not been investigated hitherto. METHODS: This study evaluated LPS/CMS-induced cognitive effects and the role of glycogen synthase kinase-3ß (GSK-3ß) activation with subsequent neuroinflammation and pathological tau deposition in the pathogenesis of these effects using lithium (Li) as a tool for GSK-3 inhibition. RESULTS: LPS pre-challenge reduced CMS-induced neuroinflammation, depressive-like behavior and cognitive inflexibility. It also improved spatial learning but increased GSK-3ß expression and exaggerated hyperphosphorylated tau accumulation in hippocampus and prefrontal cortex. Li ameliorated CMS and LPS/CMS-induced depressive and cognitive deficits, reduced GSK-3ß over-expression and tau hyperphosphorylation, impeded neuroinflammation and enhanced neuronal survival. CONCLUSION: This study draws attention to LPS/CMS-triggered cognitive changes and highlights how prior low-dose immune challenge could develop an adaptive capacity to buffer inflammatory damage and maintain the cognitive abilities necessary to withstand threats. This work also underscores the favorable effect of Li (as a GSK-3ß inhibitor) in impeding exaggerated tauopathy and neuroinflammation, rescuing neuronal survival and preserving cognitive functions. Yet, further in-depth studies utilizing different low-dose LPS challenge schedules are needed to elucidate the complex interactions between immune activation and chronic stress exposure.
Assuntos
Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/prevenção & controle , Depressão/prevenção & controle , Encefalite/prevenção & controle , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Hipocampo/efeitos dos fármacos , Cloreto de Lítio/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Tauopatias/prevenção & controle , Animais , Córtex Cerebral/enzimologia , Córtex Cerebral/fisiopatologia , Doença Crônica , Disfunção Cognitiva/enzimologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Depressão/enzimologia , Depressão/etiologia , Depressão/fisiopatologia , Modelos Animais de Doenças , Encefalite/enzimologia , Encefalite/etiologia , Encefalite/fisiopatologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/enzimologia , Hipocampo/fisiopatologia , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Masculino , Fosforilação , Ratos Wistar , Aprendizagem Espacial/efeitos dos fármacos , Estresse Psicológico/complicações , Estresse Psicológico/psicologia , Tauopatias/enzimologia , Tauopatias/etiologia , Tauopatias/fisiopatologia , Proteínas tau/metabolismoRESUMO
Accumulating evidence indicates the role of microglial activation and sustained neuroinflammation in the pathogenesis of cognitive dysfunction, a common feature associated with depressive disorders. It also indicates the role of Wnt/ß-catenin pathway in regulation of microglia-mediated neuroinflammation. Amisulpride exhibits antidepressant and pro-cognitive activities in several clinical and experimental studies. Hitherto, the direct effects of amisulpride on Wnt/ß-catenin signaling and microglial activity have not been thoroughly studied. This study aimed at investigating the effects of chronic amisulpride treatment on Wnt/ß-catenin signaling and pro-inflammatory microglial activation and its role in alleviation of depressive-like behavior and cognitive deficits elicited by unpredictable chronic mild stress (UCMS). The effects of amisulpride (3â¯mg/kg/day) were investigated on behavioral/cognitive deficits, expression of Wnt/ß-catenin pathway and microglial activation in the prefrontal cortex (PFC) of UCMS-exposed male Wistar rats. UCMS induced depressive-like behavior with impairment of performance in novel object recognition test and attentional set-shifting task. These behavioral deficits were associated with decreased total ß-catenin and increased pro-inflammatory microglial activation. Amisulpride improved UCMS-induced behavioral/cognitive deficits, ameliorated Wnt/ß-catenin signaling dysregulation and pro-inflammatory microglial activation. This work highlights the antidepressant and pro-cognitive effects of amisulpride in UCMS-exposed rats that could be mediated by modulation of Wnt/ß-catenin pathway activity and amelioration of pro-inflammatory microglial activation in the prefrontal cortex. This could provide new insights into the putative mechanisms behind the antidepressant and pro-cognitive effects exerted by amisulpride.
Assuntos
Amissulprida/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Microglia/efeitos dos fármacos , Nootrópicos/uso terapêutico , Córtex Pré-Frontal/efeitos dos fármacos , Estresse Psicológico/psicologia , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Atenção/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Depressão/prevenção & controle , Depressão/psicologia , Encefalite/tratamento farmacológico , Encefalite/psicologia , Ativação de Macrófagos , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , beta Catenina/antagonistas & inibidores , beta Catenina/biossínteseRESUMO
Microglial in vivo production of pro-inflammatory cytokines is central to the pathogenesis of multiple neurological disorders including depression, with a rising role of Wnt/ß-catenin signaling as potential regulator of microglia-mediated neuro-inflammation. This study aimed at investigating the hippocampal expression of the Wnt/ß-catenin pathway in chronic mild stress (CMS)-exposed rats and the effects of Lithium (Li) on the expression of this pathway as a method to identify a plausible link between exposure to chronic stress, microglial activation, and neuroinflammation. METHODS: The effect of chronic administration of Li was investigated on behavioral changes, hippocampal expression of Wnt-DVL-GSK3ß-ß-catenin signaling pathway, and microglial activation in CMS-exposed male Wistar rats RESULTS: CMS induced a depressive-like behavior associated with increased pro-inflammatory microglial activation and reduced hippocampal expression of the Wnt/ß-catenin signaling pathway. Chronic Li treatment ameliorated stress induced-behavioral changes, reduced microglial activation and enhanced the hippocampal expression of Wnt/ß-catenin signaling pathway. CONCLUSION: This work highlights that Li-induced inhibition of GSK-3ß with subsequent accumulation of ß-catenin could impede pro-inflammatory microglia activation which is a key pathological hallmark associated with depression. Wnt/ß-catenin signaling represents a promising therapeutic target, not only for alleviation of depression, but also for a wide array of neurological disorders.
Assuntos
Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Lítio/farmacologia , Estresse Fisiológico/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Ratos , Ratos WistarRESUMO
Depression and cardiovascular disease (CVD) are two faces of one coin. A pro-inflammatory state was previously suggested in the pathology of both diseases. We investigated the effect of chronic administration (2 weeks) of imipramine (20 mg/kg/day) and pentoxifylline (50 mg/kg/day) on behavioral, aortic histological abnormalities, and level of circulating endothelial progenitor cells (CEPCs) in peripheral blood of male Wistar rats exposed to chronic mild stress (CMS) and high-fat diet. Exposure to CMS and high-fat diet induced a depressive-like behavior alongside aortic immunohistochemical changes associated with an increase in aortic TNF-α level. Markers of CEPCs, VEGFR-2 and CD133, were significantly disturbed in aortic sections, as compared to control animals and those exposed to CMS while fed high-fat diet, although flowcytometric analysis did not show any significant changes in the level of CEPCs in peripheral blood. Chronic pentoxifylline treatment was more effective in ameliorating the histological changes and endothelial damage compared to imipramine. Pro-inflammatory cytokines-induced disturbances in CEPCs could constitute a plausible link between depression and atherosclerotic cardiovascular disease. Current antidepressants reduce symptoms of depression without tackling the underlying link between it and cardiovascular disease. Targeting pro-inflammatory cytokines might open a new therapeutic approach to alleviate depression and reduce the risk of mortality from cardiovascular disease.