ORESTES VICENTE FORLENZA
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Psiquiatria, Faculdade de Medicina - Docente
LIM/27 - Laboratório de Neurociências, Hospital das Clínicas, Faculdade de Medicina
LIM/27 - Laboratório de Neurociências, Hospital das Clínicas, Faculdade de Medicina
25 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 25
- Mitochondrial dysfunction in Alzheimer's disease: Therapeutic implications of lithium(2021) SINGULANI, Monique P.; PAULA, Vanessa J. R. De; FORLENZA, Orestes V.Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by the accumulation of abnormal tau proteins within neurons and amyloid plaques in the brain parenchyma, which leads to progressive loss of neurons in the brain. While the detailed mechanism of the pathogenesis of AD is still unknown, evidence suggests that mitochondrial dysfunction likely plays a fundamental role in the pathogenesis of this disease. Due to the relevance of mitochondrial alterations in AD, recent works have suggested the therapeutic potential of mitochondrial-targeted lithium. Lithium has been shown to possess neuroprotective and neurotrophic properties that could also be related to the upregulation of mitochondrial function. In the current work, we perform a comprehensive investigation of the significance of mitochondrial dysfunction in AD and pharmacological treatment with lithium as imperative in this pathology, through a brief review of the major findings on the effects of lithium as a therapeutic approach targeting mitochondria in the context of AD.
- Does Lithium Prevent Alzheimer's Disease?(2012) FORLENZA, Orestes V.; PAULA, Vanessa J. de; MACHADO-VIEIRA, Rodrigo; DINIZ, Breno S.; GATTAZ, Wagner F.Lithium salts have a well-established role in the treatment of major affective disorders. More recently, experimental and clinical studies have provided evidence that lithium may also exert neuroprotective effects. In animal and cell culture models, lithium has been shown to increase neuronal viability through a combination of mechanisms that includes the inhibition of apoptosis, regulation of autophagy, increased mitochondrial function, and synthesis of neurotrophic factors. In humans, lithium treatment has been associated with humoral and structural evidence of neuroprotection, such as increased expression of anti-apoptotic genes, inhibition of cellular oxidative stress, synthesis of brain-derived neurotrophic factor (BDNF), cortical thickening, increased grey matter density, and hippocampal enlargement. Recent studies addressing the inhibition of glycogen synthase kinase-3 beta (GSK3B) by lithium have further suggested the modification of biological cascades that pertain to the pathophysiology of Alzheimer's disease (AD). A recent placebo-controlled clinical trial in patients with amnestic mild cognitive impairment (MCI) showed that long-term lithium treatment may actually slow the progression of cognitive and functional deficits, and also attenuate Tau hyperphosphorylation in the MCI-AD continuum. Therefore, lithium treatment may yield disease-modifying effects in AD, both by the specific modification of its pathophysiology via inhibition of overactive GSK3B, and by the unspecific provision of neurotrophic and neuroprotective support. Although the clinical evidence available so far is promising, further experimentation and replication of the evidence in large scale clinical trials is still required to assess the benefit of lithium in the treatment or prevention of cognitive decline in the elderly.
- Neuronal-Glial Interaction in a Triple-Transgenic Mouse Model of Alzheimer's Disease: Gene Ontology and Lithium Pathways (vol 14, 579984, 2020)(2021) ROCHA, Nicole Kemberly R.; THEMOTEO, Rafael; BRENTANI, Helena; FORLENZA, Orestes V.; PAULA, Vanessa De Jesus Rodrigues De
- Antipsychotics preserve telomere length in peripheral blood mononuclear cells after acute oxidative stress injury(2022) POLHO, Gabriel B.; CARDILLO, Giancarlo M.; KERR, Daniel S.; CHILE, Thais; GATTAZ, Wagner F.; FORLENZA, Orestes V.; BRENTANI, Helena P.; DE-PAULA, Vanessa J.Antipsychotics may prolong or retain telomere length, affect mitochondrial function, and then affect the metabolism of nerve cells. To validate the hypothesis that antipsychotics can prolong telomere length after oxidative stress injury, leukocytes from healthy volunteers were extracted using Ficoll-Histopaque density gradient. The mononuclear cells layer was resuspended in cell culture medium. Oxidative stress was induced with hydrogen peroxide in cultured leukocytes. Four days later, leukocytes were treated with aripiprazole, haloperidol or clozapine for 7 days. Real-time PCR revealed that treatments with aripiprazole and haloperidol increased the telomere length by 23% and 20% in peripheral blood mononuclear cells after acute oxidative stress injury. These results suggest that haloperidol and aripiprazole can reduce the damage to telomeres induced by oxidative stress.
conferenceObject Effect of lithium at therapeutic and subtherapeutic doses in GSK3beta autonomous pathways at primary hippocampal neurons cell culture(2019) DE-PAULA, Vanessa; BARBOSA, Andre; FORLENZA, Orestes; BRENTANI, Helena- Chronic Lithium Treatment Increases Telomere Length in Parietal Cortex and Hippocampus of Triple-Transgenic Alzheimer's Disease Mice(2018) CARDILLO, Giancarlo de Mattos; DE-PAULA, Vanessa de Jesus Rodrigues; IKENAGA, Eliza Hiromi; COSTA, Luciana Rodrigues; CATANOZI, Sergio; SCHAEFFER, Evelin Lisete; GATTAZ, Wagner Farid; KERR, Daniel Shikanai; FORLENZA, Orestes VicenteTelomere length (TL) is a biomarker of cell aging, and its shortening has been linked to several age-related diseases. In Alzheimer's disease (AD), telomere shortening has been associated with neuroinflammation and oxidative stress. The majority of studies on TL in AD were based on leucocyte DNA, with little information about its status in the central nervous system. In addition to other neuroprotective effects, lithium has been implicated in the maintenance of TL. The present study aims to determine the effect of chronic lithium treatment on TL in different regions of the mouse brain, using a triple-transgenic mouse model (3xTg-AD). Eighteen transgenic and 22 wild-type (Wt) male mice were treated for eight months with chow containing 1.0 g (Li1) or 2.0 g (Li2) of lithium carbonate/kg, or standard chow (Li0). DNA was extracted from parietal cortex, hippocampus and olfactory epithelium and TL was quantified by real-time PCR. Chronic lithium treatment was associated with longer telomeres in the hippocampus (Li2, p = 0.0159) and in the parietal cortex (Li1, p = 0.0375) of 3xTg-AD compared to Wt. Our findings suggest that chronic lithium treatment does affect telomere maintenance, but the magnitude and nature of this effect depend on the working concentrations of lithium and characteristics of the tissue. This effect was observed when comparing 3xTg-AD with Wt mice, suggesting that the presence of AD pathology was required for the lithium modulation of TL.
- Medical cannabinoids for treatment of neuropsychiatric symptoms in dementia: a systematic review(2021) STELLA, Florindo; VALIENGO, Leandro C. Lane; PAULA, Vanessa J. R. de; LIMA, Carlos Augusto de Mendonca; FORLENZA, Orestes V.Introduction: Neuropsychiatric symptoms are an integral component of the natural history of dementia, occurring from prodromal to advanced stages of the disease process and causing increased burden and morbidity. Clinical presentations are pleomorphic and clinical management often requires combinations of pharmacological and non-pharmacological interventions. However, limited efficacy and a non-negligible incidence of adverse psychotropic drug events emphasize the need for novel therapeutic options. Objectives: To review the evidence supporting use of medical cannabinoids for treatment of neuropsychiatric symptoms (NPS) of dementia. Methods: We conducted a systematic review of the medical literature to examine scientific publications reporting use of medical cannabinoids for treatment of NPS. Medical Subject Headings (MeSH) were used to search for relevant publications and only papers reporting original clinical information were included. A secondary search was performed within selected publications to capture relevant citations that were not retrieved by the systematic review. The papers selected were categorized according to the level of evidence generated by the studies in relation to this clinical application, i.e. (1) controlled clinical trials; (2) open-label or observational studies; and (3) case reports. Results: Fifteen publications with original clinical data were retrieved: five controlled clinical trials, three open-label/observational studies, and seven case reports. Most studies indicated that use of medical cannabinoids engendered favorable outcomes for treatment of NPS related to moderate and advanced stages of dementia, particularly agitation, aggressive behavior, sleep disorder, and sexual disinhibition. Conclusion: Medical cannabinoids constitute a promising pharmacological approach to treatment of NPS with preliminary evidence of benefit in at least moderate to severe dementia. Controlled trials with longitudinal designs and larger samples are required to examine the long-term efficacy of these drugs in different types and stages of dementia, in addition to their adverse events and risk of interactions with other drugs. Many pharmacological details are yet to be determined, such as dosing, treatment duration, and concentrations of active compounds (e.g., cannabidiol [CBD]/Delta(9)-tetrahydrocannabinol [THC] ratio) in commercial preparations of medical cannabinoids.
- Relevance of gutmicrobiota in cognition, behaviour and Alzheimer's disease(2018) DE-PAULA, Vanessa de J. R.; FORLENZA, Andrea S.; FORLENZA, Orestes V.Approximately 95% of the symbiotic microbes in human body are located in the gut. This microbioma is involved in important homeostatic processes, not only related to gastrointestinal function but also to several complex modulatory processes, such as glucose and bone metabolism, inflammation and immune response, peripheral (enteric) and central neurotransmission. For that reason, recent studies proposed that abnormalities in gut microbiota may play a role in systemic and central nervous system (CNS) conditions. Therefore, the integrity of gut microbiota be relevant to the pathophysiology and control of important medical diseases like diabetes mellitus, inflammatory and autoimmune diseases, and even neuropsychiatric disorders such as depression, autism spectrum disorder, Parkinson's and Alzheimer disease. Gut microbiota may affect brain function and behaviour through the microbiota-gut-brain axis, in bidirectional interplay with top-down and bottom-up regulations. Through metabolic activity of non- pathogenical microorganisms and secretion of functional by-products that increase the permeability of the intestinal mucosa, the gut microbiota influences both the production and absorption of neurotransmitters (e.g., serotonin and GABA), increasing their bioavailability to the CNS. It has been further shown some components of the gut microbiota predominantly bacteria synthesize and release amyloid peptides and lipopolysaccharides, which in turn activate inflammatory signalling through the release of cytokines, with potential effects on the pathophysiological cascade of Alzheimer disease.
- Effects of a multidisciplinar cognitive rehabilitation program for patients with mild Alzheimer's disease(2011) VIOLA, Luciane F.; NUNES, Paula V.; YASSUDA, Monica S.; APRAHAMIAN, Ivan; SANTOS, Franklin S.; SANTOS, Glenda D.; BRUM, Paula S.; BORGES, Sheila M.; OLIVEIRA, Alexandra M.; CHAVES, Gisele F. S.; CIASCA, Eliane C.; FERREIRA, Rita C. R.; PAULA, Vanessa J. R. de; TAKEDA, Oswaldo H.; MIRANDEZ, Roberta M.; WATARI, Ricky; FALCAO, Deusivania V. S.; CACHIONI, Meire; FORLENZA, Orestes V.OBJECTIVE: To evaluate the effects of a multidisciplinary rehabilitation program on cognition, quality of life, and neuropsychiatric symptoms in patients with mild Alzheimer's disease. METHOD: The present study was a single-blind, controlled study that was conducted at a university-based day-hospital memory facility. The study included 25 Alzheimer's patients and their caregivers and involved a 12-week stimulation and psychoeducational program. The comparison group consisted of 16 Alzheimer's patients in waiting lists for future intervention. INTERVENTION: Group sessions were provided by a multiprofessional team and included memory training, computer-assisted cognitive stimulation, expressive activities (painting, verbal expression, writing), physiotherapy, and physical training. Treatment was administered twice a week during 6.5-h gatherings. MEASUREMENTS: The assessment battery comprised the following tests: Mini-Mental State Examination, Short Cognitive Test, Quality of Life in Alzheimer's disease, Neuropsychiatric Inventory, and Geriatric Depression Scale. Test scores were evaluated at baseline and the end of the study by raters who were blinded to the group assignments. RESULTS: Measurements of global cognitive function and performance on attention tasks indicated that patients in the experimental group remained stable, whereas controls displayed mild but significant worsening. The intervention was associated with reduced depression symptoms for patients and caregivers and decreased neuropsychiatric symptoms in Alzheimer's subjects. The treatment was also beneficial for the patients' quality of life. CONCLUSION: This multimodal rehabilitation program was associated with cognitive stability and significant improvements in the quality of life for Alzheimer's patients. We also observed a significant decrease in depressive symptoms and caregiver burden. These results support the notion that structured nonpharmacological interventions can yield adjunct and clinically relevant benefits in dementia treatment.
- Lithium, a Therapy for AD: Current Evidence from Clinical Trials of Neurodegenerative Disorders(2016) FORLENZA, Orestes V.; APRAHAMIAN, Ivan; PAULA, Vanessa J. de; HAJEK, TomasBackground: Preclinical studies have shown that lithium modifies pathological cascades implicated in certain neurodegenerative disorders, such as Alzheimer's disease (AD), Huntigton's disease (HD), multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS). A critical question is whether these pharmacodynamic properties of lithium translate into neurodegenerative diseases modifying effects in human subjects. Methods: We reviewed all English controlled clinical trials published in PubMed, PsycINFO, Embase, SCOPUS, ISI-Web with the use of lithium for the treatment of neurodegenerative disorders between July 2004 and July 2014. Results: Lithium showed evidence for positive effects on cognitive functions and biomarkers in amnestic mild cognitive impairment (aMCI, 1 study) and AD (2 studies), even with doses lower than those used for mood stabilisation. Studies of Li in HD, MSA and CSI did not show benefits of lithium. However, due to methodological limitations and small sample size, these studies may be inconclusive. Studies in ALS showed consistently negative results and presented evidence against the use of lithium for the treatment of this disease. Conclusion: In absence of disease modifying treatments for any neurodegenerative disorders, the fact that at least 3 studies supported the effect of lithium in aMCI/AD is noteworthy. Future studies should focus on defining the dose range necessary for neuroprotective effects to occur.
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