scholarly journals Antioxidant Properties of Second-Generation Antipsychotics: Focus on Microglia

2020 ◽  
Vol 13 (12) ◽  
pp. 457
Author(s):  
Giuseppe Caruso ◽  
Margherita Grasso ◽  
Annamaria Fidilio ◽  
Fabio Tascedda ◽  
Filippo Drago ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
First Generation ◽  
Second Generation ◽  
Therapeutic Potential ◽  
Antioxidant Properties ◽  
Serum Levels ◽  
Experimental Models ◽  
Primary Role ◽  
Second Generation Antipsychotics ◽  
Schizophrenic Patients

Recent studies suggest a primary role of oxidative stress in an early phase of the pathogenesis of schizophrenia and a strong neurobiological link has been found between dopaminergic system dysfunction, microglia overactivation, and oxidative stress. Different risk factors for schizophrenia increase oxidative stress phenomena raising the risk of developing psychosis. Oxidative stress induced by first-generation antipsychotics such as haloperidol significantly contributes to the development of extrapyramidal side effects. Haloperidol also exerts neurotoxic effects by decreasing antioxidant enzyme levels then worsening pro-oxidant events. Opposite to haloperidol, second-generation antipsychotics (or atypical antipsychotics) such as risperidone, clozapine, and olanzapine exert a strong antioxidant activity in experimental models of schizophrenia by rescuing the antioxidant system, with an increase in superoxide dismutase and glutathione (GSH) serum levels. Second-generation antipsychotics also improve the antioxidant status and reduce lipid peroxidation in schizophrenic patients. Interestingly, second-generation antipsychotics, such as risperidone, paliperidone, and in particular clozapine, reduce oxidative stress induced by microglia overactivation, decreasing the production of microglia-derived free radicals, finally protecting neurons against microglia-induced oxidative stress. Further, long-term clinical studies are needed to better understand the link between oxidative stress and the clinical response to antipsychotic drugs and the therapeutic potential of antioxidants to increase the response to antipsychotics.

Pharmakotherapie update

2020 ◽  
Vol 25 (1) ◽  
pp. 23-32
Author(s):  
Gerd Laux
Keyword(s):  
First Generation ◽  
Second Generation ◽  
Therapeutische Maßnahmen ◽  
Second Generation Antipsychotics

Für die Therapie schizophrener Erkrankungen sind seit fast 60 Jahren Antipsychotika/Neuroleptika aufgrund ihrer antipsychotischen Wirkung von zentraler Bedeutung. Die Einteilung kann unter verschiedenen Gesichtspunkten erfolgen (chemische Struktur, neuroleptische Potenz, Rezeptorprofil), heute werden üblicherweise unterschieden typische (traditionelle, klassische, konventionelle) Antipsychotika der ersten Generation ‒ »First Generation Antipsychotics« (FGA) ‒ und sog. atypische (»neuere«) Neuroleptika bzw. Antipsychotika der zweiten Generation ‒»Second Generation Antipsychotics« (SGA). Hierzu zählen Aripiprazol, Asenapin, Cariprazin, Clozapin, Olanzapin, Quetiapin, Risperidon, Sertindol und Ziprasidon. Hierbei handelt es sich um keine homogene Gruppe – sowohl neuropharmakologisch (Wirkmechanismus), als auch hinsichtlich klinischem Wirkprofil und dem Nebenwirkungsspektrum bestehen z. T. erhebliche Unterschiede. Neben der Akut-Medikation ist eine Langzeitmedikation bzw. Rezidivprophylaxe mit Antipsychotika für die Rehabilitation vieler schizophrener Patienten im Sinne eines »Stresspuffers« von grundlegender Bedeutung. In Placebo-kontrollierten Studien trat bei Patienten, die über ein Jahr behandelt wurden, bei etwa 30% unter Neuroleptika ein Rezidiv auf, unter Placebo bei mehr als 70%. Für die Langzeitbehandlung bietet sich der Einsatz von Depot-Neuroleptika an, neu entwickelt wurden Langzeit-Depot-Injektionen mit Intervallen von bis zu 3 Monaten. Grundsätzlich ist die niedrigstmögliche (wirksame) Dosis zu verwenden. Im Zentrum der Nebenwirkungen (UAW) standen lange Zeit extrapyramidal-motorische Bewegungsstörungen (EPMS), mit der Einführung von Clozapin und anderen atypischen Antipsychotika der zweiten Generation gewannen andere Nebenwirkungen an Bedeutung. Hierzu zählen Gewichtszunahme, Störungen metabolischer Parameter und ein erhöhtes Risiko für Mortalität und zerebrovaskuläre Ereignisse bei älteren Patienten mit Demenz. Entsprechende Kontrolluntersuchungen sind erforderlich, für Clozapin gibt es aufgrund seines Agranulozytose-Risikos Sonderbestimmungen. Immer sollte ein Gesamtbehandlungsplan orientiert an der neuen S3-Praxisleitlinie Schizophrenie der DGPPN aufgestellt werden, der psychologische und milieu-/sozial-therapeutische Maßnahmen einschließt. Standard ist heute auch eine sog. Psychoedukation, für Psychopharmaka liegen bewährte Patienten-Ratgeber vor.

Structurally Related Edaravone Analogues: Synthesis, Antiradical, Antioxidant, and Copper-Chelating Properties

2020 ◽  
Vol 18 (10) ◽  
pp. 779-790 ◽  
Author(s):  
Alexandre LeBlanc ◽  
Miroslava Cuperlovic-Culf ◽  
Pier Jr. Morin ◽  
Mohamed Touaibia
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Therapeutic Potential ◽  
Antioxidant Properties ◽  
Radical Scavenging ◽  
Therapeutic Options ◽  
Partial Charge ◽  
Associated Diseases ◽  
Significant Interest ◽  
Lateral Sclerosis

Background:: The current therapeutic options available to patients diagnosed with Amyotrophic Lateral Sclerosis (ALS) are limited and edaravone is a compound that has gained significant interest for its therapeutic potential in this condition. Objectives: : The current work was thus undertaken to synthesize and characterize a series of edaravone analogues. Methods: A total of 17 analogues were synthesized and characterized for their antioxidant properties, radical scavenging potential and copper-chelating capabilities. Results: Radical scavenging and copper-chelating properties were notably observed for edaravone. Analogues bearing hydrogen in position 1 and a phenyl at position 3 and a phenyl in both positions of pyrazol-5 (4H)-one displayed substantial radical scavenging, antioxidants and copper-chelating properties. High accessibility of electronegative groups combined with higher electronegativity and partial charge of the carbonyl moiety in edaravone might explain the observed difference in the activity of edaravone relative to the closely related analogues 6 and 7 bearing hydrogen at position 1 and a phenyl at position 3 (6) and a phenyl in both positions (7). Conclusion: Overall, this study reveals a subset of edaravone analogues with interesting properties. Further investigation of these compounds is foreseen in relevant models of oxidative stress-associated diseases in order to assess their therapeutic potential in such conditions.

scholarly journals In Vitro Evaluation of the Anti-Inflammatory Effect of KMUP-1 and in Vivo Analysis of Its Therapeutic Potential in Osteoarthritis

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 615
Author(s):  
Shang-En Huang ◽  
Erna Sulistyowati ◽  
Yu-Ying Chao ◽  
Bin-Nan Wu ◽  
Zen-Kong Dai ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Antioxidant Properties ◽  
Serum Levels ◽  
Gene Expressions ◽  
Tnf Α ◽  
Anti Inflammatory

Osteoarthritis is a degenerative arthropathy that is mainly characterized by dysregulation of inflammatory responses. KMUP-1, a derived chemical synthetic of xanthine, has been shown to have anti-inflammatory and antioxidant properties. Here, we aimed to investigate the in vitro anti-inflammatory and in vivo anti-osteoarthritis effects of KMUP-1. Protein and gene expressions of inflammation markers were determined by ELISA, Western blotting and microarray, respectively. RAW264.7 mouse macrophages were cultured and pretreated with KMUP-1 (1, 5, 10 μM). The productions of TNF-α, IL-6, MMP-2 and MMP- 9 were reduced by KMUP-1 pretreatment in LPS-induced inflammation of RAW264.7 cells. The expressions of iNOS, TNF-α, COX-2, MMP-2 and MMP-9 were also inhibited by KMUP-1 pretreatment. The gene expression levels of TNF and COX families were also downregulated. In addition, KMUP-1 suppressed the activations of ERK, JNK and p38 as well as phosphorylation of IκBα/NF-κB signaling pathways. Furthermore, SIRT1 inhibitor attenuated the inhibitory effect of KMUP-1 in LPS-induced NF-κB activation. In vivo study showed that KMUP-1 reduced mechanical hyperalgesia in monoiodoacetic acid (MIA)-induced rats OA. Additionally, KMUP-1 pretreatment reduced the serum levels of TNF-α and IL-6 in MIA-injected rats. Moreover, macroscopic and histological observation showed that KMUP-1 reduced articular cartilage erosion in rats. Our results demonstrated that KMUP-1 inhibited the inflammatory responses and restored SIRT1 in vitro, alleviated joint-related pain and cartilage destruction in vivo. Taken together, KMUP-1 has the potential to improve MIA-induced articular cartilage degradation by inhibiting the levels and expression of inflammatory mediators suggesting that KMUP-1 might be a potential therapeutic agent for OA.

Antipsychotic utilisation and persistence in Australia: A nationwide 5-year study

2021 ◽  
pp. 000486742110516
Author(s):  
Mark Taylor ◽  
Dante Dangelo-Kemp ◽  
Dennis Liu ◽  
Steve Kisely ◽  
Simon Graham ◽  
...  
Keyword(s):  
First Generation ◽  
Second Generation ◽  
Treatment Persistence ◽  
Persistence Time ◽  
Hazard Ratios ◽  
Second Generation Antipsychotics ◽  
Time In Treatment ◽  
Second Generation Antipsychotic ◽  
Long Acting ◽  
Subsequent Relapse

Objectives: To evaluate the utilisation and persistence of antipsychotics for the treatment of schizophrenia in Australia. Methods: A retrospective study using the Australian Pharmaceutical Benefits Scheme database of a representative 10% sample. All adults with schizophrenia who were dispensed three or more supplies of oral (including clozapine) or long-acting injectable antipsychotics between 1 June 2015 and 31 May 2020 were included. Persistence time in treatment was evaluated using survival analysis and Cox hazard ratios. Results: In all, 26,847 adults with schizophrenia were studied. Oral second-generation antipsychotics were more frequently dispensed than the other antipsychotic groups studied. Median treatment persistence times were 18.3 months for second-generation antipsychotic long-acting injectables, 10.7 months for oral second-generation antipsychotics and were significantly lower for both formulations of first-generation antipsychotics at 5.2 months (long-acting injectables) and 3.7 months (oral). The median persistence time for clozapine was significantly longer than all other antipsychotics groups. Conclusions: Oral second-generation antipsychotics and second-generation antipsychotic long-acting injectables accounted for over 75% and 13% of all antipsychotics in Australia, respectively. Concerns over medication adherence and subsequent relapse have not translated into increased long-acting injectable usage despite their significantly longer persistence. Clozapine, the single most ‘persistent’ antipsychotic, was only used in 9% of people, although up to a third of all cases are likely to be treatment-resistant. Our data suggest clinicians should give consideration to the earlier use of second-generation antipsychotic long-acting injectables and clozapine, to ameliorate prognosis in schizophrenia.

scholarly journals An investigation of oxidant/antioxidant balance in patients with migraine: a case-control study

BMC Neurology ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Mansoureh Togha ◽  
Soodeh Razeghi Jahromi ◽  
Zeinab Ghorbani ◽  
Amir Ghaemi ◽  
Pegah Rafiee
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Enzymes ◽  
Antioxidant Capacity ◽  
Pearson Correlation ◽  
Antioxidant Properties ◽  
Serum Levels ◽  
Trolox Equivalent Antioxidant Capacity ◽  
P Value ◽  
And Control ◽  
Chronic Migraineurs

Abstract Background In recent years, the role of neuroinflammation and oxidative stress in migraine pathogenesis has achieved considerable interest; however, to date findings are equivocal. Thus, the objective of this study was to investigate biomarkers of oxidative stress in episodic and chronic migraineurs (EM and CM patients) and controls. Methods Forty-four patients with EM, 27 individuals with CM and 19 age-sex-matched controls were enrolled. After collecting data on demographic and headache characteristics, blood samples were collected and analyzed to detect serum levels of oxidative stress biomarkers (malondialdehyde (MDA) and nitric oxide (NO)); total antioxidant capacity using Trolox equivalent antioxidant capacity (TEAC) assay; and antioxidant enzymes (catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase-1 (GPx-1)). Results Serum levels of CAT and SOD were significantly lower in the CM group than the EM group and controls. However, serum GPx-1 levels of the CM patients were slightly higher than the EM patients and controls (P-value≤0.001). CM patients had lower mean TEAC values than EM patients and controls. In addition, serum levels of NO and MDA were significantly elevated among subjects with CM compared to EM and control individuals (P-value≤0.001). Pearson correlation analysis revealed negative correlations between the number of days of having headaches per month and serum concentrations of the two antioxidant enzymes CAT (r = − 0.60, P-value< 0.001) and SOD (r = − 0.50, P-value< 0.001) as well as TEAC values (r = − 0.61, P-value< 0.001); however, there were positive correlations between headache days and serum GPx-1 levels (r = 0.46, P-value< 0.001), NO (r = 0.62, P-value< 0.001), and MDA (r = 0.64, P-value< 0.001). Conclusion Present findings highlighted that chronic migraineurs had lower total non-enzymatic antioxidant capacity and higher oxidative stress than episodic migraineurs and control individuals. Although more studies are needed to confirm these data, applying novel prophylactic medications or dietary supplements with antioxidant properties could be promising in migraine therapy.

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