Pain is underdiagnosed and often not adequately treated, contributing to behavioral and psychological symptoms of dementia (BPSD). BPSD are treated with atypical antipsychotics that are associated ...with severe cerebrocardiovascular effects. Interestingly, treatment of pain may reduce agitation. Research is focusing on nonpharmacological treatment, such as aromatherapy, for pain and BPSD in dementia. This clinical study will assess the effect on agitation in severely demented elderly of BEO loaded in a nanotechnological odorless cream indistinguishable from placebo. This is a protocol for a randomized, double‐blind, placebo‐controlled trial (NCT04321889). A total of 134 patients aged ≥65 years with severe dementia (mini‐mental state examination <12) will be recruited and randomly allocated 1:1 to either BEO or placebo group. After baseline screening, BEO (80 mg) cream or placebo cream will be trans‐dermally applied on both arms twice a day for 4 weeks with a 4‐week follow‐up period. The effect on agitation will be the primary endpoint. Any adverse events will be reported. A double‐blind, clinical trial evaluating efficacy and safety of an essential oil endowed with strong analgesic properties has never been carried out before. This study could form the basis for a safer and more effective treatment of BPSD in severe dementia.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background: Open Angle Glaucoma (POAG) is the leading causes of irreversible blindness
worldwide. Elevated intraocular pressure is considered an important risk factor for glaucoma; however,
a subset ...of patients experiences a progression of the disease even in presence of normal intraocular
pressure values. This implies that risk factors other than intraocular pressure are involved in the
pathogenesis of glaucoma. A possible relationship between glaucoma and neurodegenerative diseases
such as Alzheimer Disease has been suggested. In this regard, we recently described a high prevalence
of alterations typical of glaucoma, using Heidelberg Retinal Tomograph-3, in a group of patients with
Alzheimer Disease. Interestingly, these alterations were not associated with elevated intraocular pressure
or abnormal Central Corneal Thickness values. Alzheimer Disease is the most common form of
dementia with progressive deterioration of memory and cognition. Complaints related to vision are
common among Alzheimer Disease patients.
Methods: In this paper researches related to glaucoma and Alzheimer disease are reviewed.
Results: Diseases characteristics, i.e. common features, risk factors and pathophysiological mechanisms
gathered in the recent literature do suggest that Alzheimer Disease and glaucoma can be considered
both age-related neurodegenerative diseases that may co-exist in the elderly.
Conclusion: In conclusion, preclinical and clinical evidence gathered so far support the notion that
glaucoma is a widespread neurodegenerative condition whose common pathogenetic mechanisms with
other diseases, i.e. Alzheimer Disease, should be further investigated as they may shed new light on
these diseases improving both diagnosis and treatments.
To develop novel and effective treatments for ischemic stroke, we investigated the neuroprotective effects of the macrolide antibiotic azithromycin in a mouse model system of transient middle ...cerebral artery occlusion. Intraperitoneal administration of azithromycin significantly reduced blood–brain barrier damage and cerebral infiltration of myeloid cells, including neutrophils and inflammatory macrophages. These effects resulted in a dose-dependent reduction of cerebral ischemic damage, and in a remarkable amelioration of neurological deficits up to 7days after the insult. Neuroprotection was associated with increased arginase activity in peritoneal exudate cells, which was followed by the detection of Ym1- and arginase I-immunopositive M2 macrophages in the ischemic area at 24–48h of reperfusion. Pharmacological inhibition of peritoneal arginase activity counteracted azithromycin-induced neuroprotection, pointing to a major role for drug-induced polarization of migratory macrophages towards a protective, non-inflammatory M2 phenotype.
•Azithromycin dose-dependently reduces brain damage caused by MCAo in mice.•Azithromycin reduces brain infiltration of neutrophils and inflammatory macrophages.•Neuroprotection is associated with elevation of brain and peritoneal M2 macrophages.•Inhibition of arginase activity counteracted azithromycin-induced neuroprotection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abnormal neuronal and synaptic plasticity occurs in Alzheimer's disease (AD) and depression. The latter, particularly late-life, has been recognized as fundamental in the identification of at-risk ...prodromal stages of AD. The lack of disease-modifying drugs and the off-label use of antipsychotics and antidepressants for neuropsychiatric symptoms (NPSs) have caused a season of therapeutic inappropriateness. To date, the wealth of clinical trials investigating drugs, diverse for structure and mechanism of action, has failed to provide a cure for all the spectrums of NPSs. Psychedelics in microdosing afford promotion of neurogenesis and synaptic plasticity and, recently, have been considered a revolution for the management of depression endowed with faster action and an improved side effect profile than antidepressants. In the current scenario, therefore, the rapid-acting antidepressant esketamine could represent the first-in-class for treatment of NPSs, and this deserves to be demonstrated with an open-label clinical trial.
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•Neuropsychiatric symptoms (e.g. depression) may precede Alzheimer's disease diagnosis.•Off-label antidepressants are often used with limited efficacy and safety.•Rapid-acting antidepressants show robust neurotrophic and anti-inflammatory properties.•A case exists for rapid-acting antidepressants to be trialed in open-label studies for safety and efficacy assessment in Alzheimer's disease neuropsychiatric symptoms.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Autophagy, the cellular process responsible for degradation and recycling of cytoplasmic components through the autophagosomal-lysosomal pathway, is fundamental for neuronal homeostasis and its ...deregulation has been identified as a hallmark of neurodegeneration. Retinal hypoxic-ischemic events occur in several sight-treating disorders, such as central retinal artery occlusion, diabetic retinopathy, and glaucoma, leading to degeneration and loss of retinal ganglion cells. Here we analyzed the autophagic response in the retinas of mice subjected to ischemia induced by transient elevation of intraocular pressure, reporting a biphasic and reperfusion time-dependent modulation of the process. Ischemic insult triggered in the retina an acute induction of autophagy that lasted during the first hours of reperfusion. This early upregulation of the autophagic flux limited RGC death, as demonstrated by the increased neuronal loss observed in mice with genetic impairment of basal autophagy owing to heterozygous ablation of the autophagy-positive modulator Ambra1 (Ambra1
). Upregulation of autophagy was exhausted 24 h after the ischemic event and reduced autophagosomal turnover was associated with build up of the autophagic substrate SQSTM-1/p62, decreased ATG12-ATG5 conjugate, ATG4 and BECN1/Beclin1 expression. Animal fasting or subchronic systemic treatment with rapamycin sustained and prolonged autophagy activation and improved RGC survival, providing proof of principle for autophagy induction as a potential therapeutic strategy in retinal neurodegenerative conditions associated with hypoxic/ischemic stresses.
Aging of the population makes of dementia a challenge for health systems worldwide. The cognitive disturbance is a serious but not the only issue in dementia; behavioral and psychological syndromes ...known as neuropsychiatric symptoms of dementia remarkably reduce the quality of life. The cluster of symptoms includes anxiety, depression, wandering, delusions, hallucinations, misidentifications, agitation and aggression. The pathophysiology of these symptoms implicates all the neurotransmitter systems, with a pivotal role for the glutamatergic neurotransmission. Imbalanced glutamatergic and GABAergic neurotransmissions, over-activation of the extrasynaptic N-methyl-D-aspartate (NMDA) receptors and alterations of the latter have been linked to the development of neuropsychiatric symptoms experienced by almost the entire demented population. Drugs with efficacy and safety for prevention or long term treatment of these disorders are not available yet. Aromatherapy provides the best evidence for positive outcomes in the control of agitation, the most resistant symptom. Demented patients often cannot verbalize pain, resulting in unrelieved symptoms and contributing to agitation. Bergamot essential oil provides extensive preclinical evidence of analgesic properties. Incidentally, the essential oil of bergamot induces anxyolitic-like effects devoid of sedation, typical of benzodiazepines, with a noteworthy advantage for demented patients. These data, together with the reported safety profile, form the rational basis for bergamot as a neurotherapeutic to be trialed for the control of behavioral and psychological symptoms of dementia.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Migraine is a common neurologic disorder characterized by attacks consisting of unilateral, throbbing headache accompanied by photophobia, phonophobia, and nausea which remarkably reduces the ...patients' quality of life. Not migraine-specific non-steroidal anti-inflammatory drugs (NSAIDs) are effective in patients affected by mild episodic migraine whilst in moderate or severe episodic migraine and in chronic migraineurs triptans and preventative therapies are needed. Since these treatments are endowed with serious side effects and have limited effectiveness new pharmacological approaches have been investigated. The demonstrated pivotal role of calcitonin gene-related peptide (CGRP) has fostered the development of CGRP antagonists, unfortunately endowed with liver toxicity, and monoclonal antibodies (mAbs) toward circulating CGRP released during migraine attack or targeting its receptor. Currently, four mAbs, eptinezumab, fremanezumab, galcanezumab for CGRP and erenumab for CGRP canonical receptor, have been studied in clinical trials for episodic and chronic migraine. Apart from the proven effectiveness, these antibodies have resulted well tolerated and could improve the compliance of the patients due to their long half-lives allowing less frequent administrations. This study aims at investigating the still poorly clear pathogenesis of migraine and the potential role of anti-CGRP mAbs in the scenario of prophylaxis of migraine.
The molecular target and mechanism by which d-limonene induces LC3 lipidation and autophagosome formation remain elusive. Here, we report that this monoterpene rapidly enhances Ca2+ levels in SH-SY5Y ...cells; yet this effect does not lead to calpain- or caspase-mediated proteolysis of α-spectrin, nor calpain activity is required for the established enhancement of LC3-II levels by d-limonene. However, d-limonene rapidly reduced vimentin levels, an unexpected effect also induced by the autophagy inhibitor chloroquine (CQ). The magnitude of vimentin reduction parallels accumulation of LC3-II caused by a brief incubation with d-limonene or CQ. For longer exposure (48 h), d-limonene does not reduce vimentin, nor it increases LC3-II levels; conversely, a clear reduction of vimentin along with a massive accumulation of LC3-II is evident in cells treated with CQ. Vimentin participates in organelle positioning and in other cellular processes that have linked this intermediate filament protein to various diseases, including cancer, inflammatory and autoimmune disorders, and to virus replication and internalization. Our findings suggest an inverse relationship between vimentin reduction and LC3-II accumulation, whose causal link needs to be examined. Further experiments are needed to dissect the role of vimentin reduction in the mechanisms through which CQ impairs fusion of autophagosome with lysosomes as well as in other effects of this drug.
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•The mechanism by which d-limonene induces LC3 lipidation remains elusive.•d-Limonene rapidly enhances Ca2+ levels but not calpain activity in SH-SY5Y cells.•d-Limonene reduces vimentin levels rapidly but transiently.•The autophagy inhibitor chloroquine reduces vimentin levels in a long-lasting way.•Vimentin reduction and LC3-II accumulation appear to be inversely related.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Alzheimer’s disease (AD) and epilepsy are common neurological disorders in the elderly. A bi-directional link between these neurological diseases has been reported, with patients with either ...condition carrying almost a two-fold risk of contracting the other compared to healthy subjects. AD/epilepsy adversely affects patients’ quality of life and represents a severe public health problem. Thus, identifying the relationship between epilepsy and AD represents an ongoing challenge and continuing need. Seizures in AD patients are often unrecognized because they are often nonconvulsive and sometimes mimic some behavioral symptoms of AD. Regarding this, it has been hypothesized that epileptogenesis and neurodegeneration share common underlying mechanisms. Targeted treatment to decrease epileptiform activity could represent a valuable strategy for delaying the neurodegenerative process and related cognitive impairment. Several preclinical studies have shown that some antiseizure medications (ASMs) targeting abnormal network hyperexcitability may change the natural progression of AD. However, to date, no guidelines are available for managing seizures in AD patients because of the paucity of randomized clinical trials sufficient for answering the correlated questions. Future AD clinical studies are mandatory to update clinicians about the symptomatic treatment of seizures in AD patients and recognize whether ASM therapy could change the natural progression of the disease, thereby rescuing cognitive performance.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Post-stroke pain is one of the most common
of stroke, which stands among the leading causes of death and adult-acquired disability worldwide. The role and clinical efficacy of opioids in post-stroke ...pain syndromes is still debated.
Due to the important gap in knowledge on the management of post-stroke pain, this systematic review aimed at assessing the efficacy of opioids in post-stroke pain syndromes.
A literature search was conducted on databases relevant for medical scientific literature, i.e. PubMed/MEDLINE, Scopus, Web of Science and Cochrane Library databases from databases inception until August 31
, 2020 for clinical trials assessing the effects of opioids and opioid antagonists on pain reduction and pain related symptoms in patients with post-stroke pain syndromes. Studies assessing the effects of other medications (e.g., tricyclic antidepressant, pregabalin) or non - pharmacological management strategies (e.g., neurostimulation techniques) were excluded. The selected studies have been subjected to examination of the risk of bias.
The literature search retrieved 83,435 results. After duplicates removal, 34,285 articles were title and abstract screened. 25 full texts were assessed and 8 articles were identified to be eligible for inclusion in the qualitative summary and narrative analysis, of which three were placebo-controlled and two were dose-response. Among placebo-controlled studies, two evaluated the analgesic effect of morphine and one assessed the effects of the opioid antagonist naloxone on patients with central post-stroke pain. With regard to dose-response studies, both were on patients with central post-stroke pain, one assessing the efficacy of levorphanol, and the other on naloxone. Seven out of eight included studies showed an overall slight analgesic effect of opioids, with less consistent effects on other pain-related symptoms (e.g., mood, quality of life). The randomized controlled trials were subjected to meta-analysis and rating of the quality of evidence for the two outcomes considered according to GRADE (Grading of Recommendations, Assessment, Development and Evaluations) system. The overall results are inconclusive because of the small number of studies and of patients.
The limited number of the included studies and their heterogeneity in terms of study design do not support the efficacy of opioids in post-stroke pain and in pain-related outcomes. Large double-blind randomized clinical trials with objective assessment of pain and related symptoms are needed to further investigate this topic.
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