1,721,051 research outputs found
Insulin Signaling Regulates Mitochondrial Bioenergetics in the Brain: Insight for the Development of Neurodegenerative Diseases
No full textEditorial: Oxidative stress and Alzheimer disease: where do we stand?
No full textWhere do we stand? This question emerges when think- ing of the great number of studies published so far about oxidative stress and Alzheimer disease it becomes clear that the answer to the question is not yet in our hands, despite an extensive knowledge base. After about 30 years since the first intuition (at least by referring to PubMed database) by Martins and colleagues, who proposed the observed increase of glucose-6-phosphate dehydrogenase activity in AD brain as a response to elevated brain peroxide metabolism [1], the discussion on the contribution of oxidative stress to AD on- set and progression is still open
Biliverdin Reductase-A correlates with inducible nitric oxide synthasein in atorvastatin treated aged canine brain.
No full textAlzheimer's disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug for Alzheimer's disease, but the exact mechanisms of action are still unknown. Biliverdin reductase-A is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but its serine/threonine/tyrosine kinase activity is able to modulate cell signaling networks. We previously reported the beneficial effects of atorvastatin treatment on biliverdin reductase-A and heme oxygenase-1 in the brains of a well characterized pre-clinical model of Alzheimer's disease, aged beagles, together with observed improvement in cognition. Here we extend our knowledge of the effects of atorvastatin on inducible nitric oxide synthase in parietal cortex, cerebellum and liver of the same animals. We demonstrated that atorvastatin treatment (80 mg/day for 14.5 months) to aged beagles selectively increased inducible nitric oxide synthase in the parietal cortex but not in the cerebellum. In contrast, inducible nitric oxide synthase protein levels were significantly decreased in the liver. Significant positive correlations were found between biliverdin reductase-A and inducible nitric oxide synthase as well as heme oxygenase-1 protein levels in the parietal cortex. The opposite was observed in the liver. Inducible nitric oxide synthase up-regulation in the parietal cortex was positively associated with improved biliverdin reductase-A functions, whereas the oxidative-induced impairment of biliverdin reductase-A in the liver negatively affected inducible nitric oxide synthase expression, thus suggesting a role for biliverdin reductase-A in atorvastatin-dependent inducible nitric oxide synthase changes. Interestingly, increased inducible nitric oxide synthase levels in the parietal cortex were not associated with higher oxidative/nitrosative stress levels. We hypothesize that biliverdin reductase-A-dependent inducible nitric oxide synthase regulation strongly contributes to the cognitive improvement observed following atorvastatin treatment.Alzheimer's disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug for Alzheimer's disease, but the exact mechanisms of action are still unknown. Biliverdin reductase-A is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but its serine/threonine/tyrosine kinase activity is able to modulate cell signaling networks. We previously reported the beneficial effects of atorvastatin treatment on biliverdin reductase-A and heme oxygenase-1 in the brains of a well characterized pre-clinical model of Alzheimer's disease, aged beagles, together with observed improvement in cognition. Here we extend our knowledge of the effects of atorvastatin on inducible nitric oxide synthase in parietal cortex, cerebellum and liver of the same animals. We demonstrated tha
COMPOSITIONS FOR USE IN THE PREVENTION AND/ OR TREATMENT OF INTELLECTUAL DISABILITY AND NEURODEGENERATIVE DISEASES IN A SUBJECT WITH DOWN SYNDROME
No full textDown syndrome (DS) is a condition caused by total or partial trisomy of chromosome 21, and is characterized by both physical and neurological defects, including mild to severe intellectual disability. In addition, individuals with DS have a high risk of developing neurodegenerative diseases, such as Alzheimer's disease (AD), usually starting at 40 years of age.
The recovery of the behavioral and neurophysiological deficit observed following the use of GAB AA receptor (GAB AA-R) inhibitors in mouse models of DS has led to the hypothesis that the intellectual deficit could depend on an imbalance in inhibitory circuits.
Most of the data produced so far in mouse models suggests that this imbalance may be attributable to a high number of inhibitory neurons and a higher frequency of inhibitory post-synaptic currents. At the same time, however, evidence to the contrary was also provided: in particular, the imbalance of the inhibitory circuits would cause an increase in the intracellular concentration of chlorine ions (CT) in such a way that, following activation of the GABAA receptor, a flow of Cl- ions from the inside to the outside of the cell would be observed, with consequent depolarization of the neuron and reduced inhibition.
Consequently, although alteration of GABAergic transmission is the basis of cognitive retardation in subjects with DS, the causes of this alteration are still unclear and, to date, there are no therapeutic approaches useful for improving cognitive deficit and counteracting the development of neurodegenerative diseases in individuals with DS, particularly in adulthood.
Existing products such as GABA-A receptor antagonists or reverse inhibitors are not available in the clinic; when tested on humans they did not reach the primary and secondary endpoints and the study was stopped. Furthermore, the use of broad- spectrum GABAA receptor antagonists has not been approved as they can promote convulsions and anxiety crises. Summary of the invention
The present description has the object of providing a composition that is efficient and safe for use in preventing and/or treating intellectual disability and neurodegenerative diseases in a subject with Down syndrome (DS). According to the present description, this object is achieved thanks to the subject specifically indicated in the following claims, which are intended as an integral part of this description.
One embodiment of the present description provides a composition for use in the prevention and/or in the treatment of intellectual disability and neurodegenerative diseases in a subject with DS, wherein the composition comprises - as active agent
- at least one compound belonging to the class of inhibitors of the enzyme dipeptidyl-peptidase IV (DPP4). The compound belonging to the class of DPP4 inhibitors also belongs to the class of gliptins, and may be selected in the group consisting of sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, tenegliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, glosogliptin, dutogliptin.
The present description also provides a method for treating intellectual disability and neurodegenerative diseases in a subject with DS, the method comprising the step of administering a composition to the subject comprising at least one compound belonging to the class of dipeptidyl-peptidase IV inhibitors (DPP4) as active agent.
The composition of the present description has been found to be effective not only in restoring GABAergic transmission and the cognitive deficit, but also in slowing the development of neurodegenerative diseases in subjects with DS, such as Alzheimer's disease, for example. Furthermore, the composition activates a specific molecular mechanism (described below), which in subjects with DS - unlike what has been demonstrated in healthy subjects - has been surprisingly able to promote neuroprotective (and non-neurotoxic) effects
Experimental research on nitric oxide and therapy of Alzheimer disease: a challenging bridge
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