Given that neuronal degeneration in Alzheimer's disease (AD) is caused by the combination of multiple neurotoxic insults, current directions in the research of novel therapies to treat this disease attempts to design multitarget strategies that could be more effective than the simply use of acetylcholinesterase inhibitors; currently, the most used therapy for AD. One option, explored recently, is the synthesis of new analogues of cannabinoids that could competitively inhibit the acetylcholinesterase (AChE) enzyme and showing the classic neuroprotective profile of cannabinoid compounds. In this work, molecular docking has been used to design some cannabinoid analogues with such multitarget properties, based on the similarities of donepezil and Δ-tetrahydrocannabinol.
View Article and Find Full Text PDFCell fate events are regulated by different endogenous developmental factors such as the cell micro-environment, external or remote signals and epigenetic factors. Among the many regulatory factors, endocannabinoid-associated signalling pathways are known to conduct several of these events in the developing nervous system and in the adult brain. Interestingly, endocannabinoids exert modulatory actions in both physiological and pathological conditions.
View Article and Find Full Text PDFBackground: Neuroprotection with cannabinoids in Parkinson's disease (PD) has been afforded predominantly with antioxidant or anti-inflammatory cannabinoids. In the present study, we investigated the anti-inflammatory and neuroprotective properties of VCE-003.2, a quinone derivative of the non-psychotrophic phytocannabinoid cannabigerol (CBG), which may derive its activity at the peroxisome proliferator-activated receptor-γ (PPARγ).
View Article and Find Full Text PDFA zoonotic, opportunistic out-break of tropical rat mite Ornithonyssus bacoti [Acari: Macronyssidae; Ornithonyssus bacoti (Hirst)] in an animal facility, is described. Immunocompetent mice [Mus musculus (Linnaeus)] and rat [Rattus norvegicus (Berkenhout)] strains in a conventional health status facility suffered from scratching and allopecia and staff members suffered from pruritic, erythemato-papular lesions, presumed to be allergic in origin. O.
View Article and Find Full Text PDFPrevious studies have investigated the relevance and structure-activity relationships (SARs) of pyrazole derivatives in relation with cannabinoid receptors, and the series of tricyclic 1,4-dihydroindeno[1,2-c]pyrazoles emerged as potent CB2 receptor ligands. In the present study, novel 1,4-dihydroindeno[1,2-c]pyrazole and 1H-benzo[g]indazole carboxamides containing a cyclopropyl or a cyclohexyl substituent were designed and synthesized to evaluate the influence of these structural modifications towards CB1 and CB2 receptor affinities. Among these derivatives, compound 15 (6-cyclopropyl-1-(2,4-dichlorophenyl)-N-(adamantan-1-yl)-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide) showed the highest CB2 receptor affinity (Ki = 4 nM) and remarkable selectivity (KiCB1/KiCB2 = 2232), whereas a similar affinity, within the nM range, was seen for the fenchyl derivative (compound 10: Ki = 6 nM), for the bornyl analogue (compound 14: Ki = 38 nM) and, to a lesser extent, for the aminopiperidine derivative (compound 6: Ki = 69 nM).
View Article and Find Full Text PDFDuring the last years, there has been a continuous interest in the development of cannabinoid receptor ligands that may serve as therapeutic agents and/or as experimental tools. This prompted us to design and synthesize analogues of the CB2 receptor antagonist N-fenchyl-5-(4-chloro-3-methyl-phenyl)-1-(4-methyl-benzyl)-1H-pyrazole-3-carboxamide (SR144528). The structural modifications involved the bioisosteric replacement of the pyrazole ring by a pyrrole ring and variations on the amine carbamoyl substituents.
View Article and Find Full Text PDFDesigning drugs with a specific multi-target profile is a promising approach against multifactorial illnesses as Alzheimer's disease. In this work, new indazole ethers that possess dual activity as both cannabinoid agonists CB2 and inhibitors of BuChE have been designed by computational methods. On the basis of this knowledge, the synthesis, pharmacological evaluation and docking studies of a new class of indazoles has been performed.
View Article and Find Full Text PDFInhibition of the insulin/insulin-like growth factor signalling pathway increases lifespan and protects against neurodegeneration in model organisms, and has been considered as a potential therapeutic target. This pathway is upstream of mTORC1, a negative regulator of autophagy. Thus, we expected autophagy to be activated by insulin-like growth factor-1 (IGF-1) inhibition, which could account for many of its beneficial effects.
View Article and Find Full Text PDFBim is a proapoptotic BH3-only Bcl-2 family member. In response to death stimuli, Bim dissociates from the dynein light chain 1 (DYNLL1/LC8), where it is inactive, and can then initiate Bax/Bak-mediated mitochondria-dependent apoptosis. We found that Bim depletion increases autophagosome synthesis in cells and in vivo, and this effect is inhibited by overexpression of cell death-deficient Bim.
View Article and Find Full Text PDFIn this study, we look for the existence of signal transducers and activators of transcription response elements (STATREs) in the human insulin receptor (hIR) gene promoter and their possible relation with the estradiol-provoked transcriptional repression of the hIR gene and cellular insulin resistance in U-937 human promonocytic cells. Potential STATREs in the region from -1819 to -271 bp of the hIR gene promoter were identified by their homology with the consensus STATRE (5'TTCnnnGAA3') using the SEQFIND programme developed in our laboratory. We located five virtual STATRE-like sites: [(I): -1472/-1464], [(II): -1548/-1540], [(III): -1552/-1544], [(IV): -1587/-1579] and [(V): -1678/-1670] showing a difference of only one base from this consensus.
View Article and Find Full Text PDFAutophagy, a major degradation process for long-lived and aggregate-prone proteins, affects various human processes, such as development, immunity, cancer, and neurodegeneration. Several autophagy regulators have been identified in recent years. Here we show that nitric oxide (NO), a potent cellular messenger, inhibits autophagosome synthesis via a number of mechanisms.
View Article and Find Full Text PDFAutophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. During starvation, the cell expands both compartments to enhance degradation processes. We found that starvation activates a transcriptional program that controls major steps of the autophagic pathway, including autophagosome formation, autophagosome-lysosome fusion, and substrate degradation.
View Article and Find Full Text PDFThe accumulation of misfolded proteins in insoluble aggregates within the neuronal cytoplasm is one of the common pathological hallmarks of most adult-onset human neurodegenerative diseases. The clearance of these misfolded proteins may represent a promising therapeutic strategy in these diseases. The two main routes for intracellular protein degradation are the ubiquitin-proteasome and the autophagy-lysosome pathways.
View Article and Find Full Text PDF(Macro)autophagy is a bulk degradation process that mediates the clearance of long-lived proteins and organelles. Autophagy is initiated by double-membraned structures, which engulf portions of cytoplasm. The resulting autophagosomes ultimately fuse with lysosomes, where their contents are degraded.
View Article and Find Full Text PDFFibrillar protein aggregates are the major pathological hallmark of several incurable, age-related, neurodegenerative disorders. These aggregates typically contain aggregation-prone pathogenic proteins, such as amyloid-beta in Alzheimer's disease and alpha-synuclein in Parkinson's disease. It is, however, poorly understood how these aggregates are formed during cellular aging.
View Article and Find Full Text PDFBackground: Parkinson's disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression or the A53T missense mutation of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons.
Methodology/principal Findings: Here, we used two mouse lines overexpressing human A53T-SNCA and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms.
Many neurodegenerative diseases exhibit protein accumulation and increased oxidative stress. Therapeutic strategies include clearing aggregate-prone proteins by enhancing autophagy or decreasing oxidative stress with antioxidants. Many autophagy-inducing stimuli increase reactive oxygen species (ROS), raising concerns that the benefits of autophagy up-regulation may be counterbalanced by ROS toxicity.
View Article and Find Full Text PDFAutophagy is an intracellular degradation process responsible for the clearance of most long-lived proteins and organelles. Cytoplasmic components are enclosed by double-membrane autophagosomes, which subsequently fuse with lysosomes for degradation. Autophagy dysfunction may contribute to the pathology of various neurodegenerative disorders, which manifest abnormal protein accumulation.
View Article and Find Full Text PDFCannabinoid-based medicines have been proposed as clinically promising therapies in Parkinson's disease (PD), given the prominent modulatory function played by the cannabinoid signaling system in the basal ganglia. Supporting this pharmacological potential, the cannabinoid signaling system experiences a biphasic pattern of changes during the progression of PD. Thus, early and presymptomatic stages, characterized by neuronal malfunctioning but little evidence of neuronal death, are associated with desensitization/downregulation of CB(1) receptors.
View Article and Find Full Text PDFBackground: Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD.
Methodology/principal Findings: Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age.
This study was designed to examine the type of changes experienced by the CB1 receptor, a key element of the cannabinoid signaling system, in the basal ganglia of different mouse mutants generated by deletion of specific genes associated with the development of Parkinson's disease in humans [PARK1 (alpha-synuclein), PARK2 (parkin) or PARK6 (PINK1)]. We observed that CB1 receptor-mRNA levels were significantly reduced in the caudate-putamen in the three models under examination when animals were analyzed at early phases (< or = 12 months of age). This decrease was, in general, associated with a reduction in CB1 receptor binding in the substantia nigra and the globus pallidus, particularly in the case of alpha-synuclein-deficient mice.
View Article and Find Full Text PDFBackground: this study set out to examine the effects of the treatment with 1,25-dihydroxyvitamin D3 (1,25D3) [150 IU/Kg (3.75 microg/Kg) one a day, for 15 days] to non-diabetic rats and in rats rendered diabetic by a single injection of streptozotocin [65 mg/kg].
Results: treatment with 1,25D3 to non-diabetic rats did not affect the biochemical parameters measured in the plasma and urine of these animals.
While recent studies have shown that the blockade of cannabinoid CB(1) receptors might be beneficial to alleviate the motor inhibition typical of Parkinson's disease (PD), the neurochemical substrates for this effect remain elusive. Here we have carried out microdialysis experiments to determine whether the effects of rimonabant, a selective antagonist of CB(1) receptors, might be associated with changes in striatal glutamate release in a rat model of PD generated by intracerebroventricular injection of 6-hydroxydopamine. Our data demonstrate that the treatment with rimonabant slightly increased striatal glutamate release in control rats, although this effect was only evident with the highest dose of rimonabant tested (1mg/kg).
View Article and Find Full Text PDFCB2 receptors, the so-called peripheral cannabinoid receptor type, were first described in the immune system, but they have been recently identified in the brain in healthy conditions and, in particular, after several types of cytotoxic stimuli. Specifically, CB2 receptors were identified in microglial cells, astrocytes and, to a lesser extent, in certain subpopulations of neurons. Given the lack of psychoactivity demonstrated by selective CB2 receptor agonists, this receptor becomes an interesting target for the treatment of neurological diseases, in particular, the case of certain neurodegenerative disorders in which induction/up-regulation of CB2 receptors has been already demonstrated.
View Article and Find Full Text PDFCannabinoids have been proposed as clinically promising neuroprotective molecules, as they are capable to reduce excitotoxicity, calcium influx, and oxidative injury. They are also able to decrease inflammation by acting on glial processes that regulate neuronal survival and to restore blood supply to injured area by reducing the vasoconstriction produced by several endothelium-derived factors. Through one or more of these processes, cannabinoids may provide neuroprotection in different neurodegenerative disorders including Parkinson's disease and Huntington's chorea, two chronic diseases that are originated as a consequence of the degeneration of specific nuclei of basal ganglia, resulting in a deterioration of the control of movement.
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