Effect of Synthetic Cannabinoid HU210 on Memory Deficits and Neuropathology in Alzheimers Disease Mouse Model

Chen, B.; Bromley-Brits, Kelley; He, Guiqiong; Cai, Fei; Zhang, X.; Song, Weihong

doi:10.2174/156720510791050948

Cited by 31 publications

(25 citation statements)

References 34 publications

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“…Two previous studies also showed that the activation of CB2 receptor stimulates β-amyloid removal in vitro by human macrophages [68] and in Tg2576 mice by favoring β-amyloid transport through the choroid plexus [25]. In contrast, a recent study [69] reported no changes in β-amyloid plaque burden following subchronic treatment with the CB1/CB2 mixed agonist HU-210. This discrepancy may be due to methodological differences, since the authors of this recent study used male and female double APP23/PS1 transgenic mice aged 4 or 6-9 weeks as well as a very low dose of the cannabinoid agonist (10 or 50 μg/kg) injected twice daily [69].…”

Section: Discussionmentioning

confidence: 99%

β-Caryophyllene Ameliorates the Alzheimer-Like Phenotype in APP/PS1 Mice through CB2 Receptor Activation and the PPARγ Pathway

Cheng¹,

Dong²,

Li³

2014

Pharmacology

135

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Background/Aims: The activation of cannabinoid receptor 2 (CB2) has the beneficial effect of reducing neuroinflammatory response in the treatment of Alzheimer's disease (AD) and is suggested to trigger the peroxisome proliferator-activated receptor-γ (PPARγ) pathway; agonists of both receptors improve AD. Recently, the plant metabolite β-caryophyllene was shown to selectively bind to CB2 receptor and act as a full agonist. Methods: In this study, we examined the anti-inflammatory effect of β-caryophyllene in a transgenic APP/PS1 AD model and analyzed whether this effect was mediated by CB2 and PPARγ. Results: β-Caryophyllene, given orally, prevented cognitive impairment in APP/PS1 mice, and this positive cognitive effect was associated with reduced β-amyloid burden in both the hippocampus and the cerebral cortex. Moreover, β-caryophyllene reduced astrogliosis and microglial activation as well as the levels of COX-2 protein and the mRNA levels of the proinflammatory cytokines tumor necrosis factor-α and interleukin-1β in the cerebral cortex. The use of the CB2 antagonist AM630 or the PPARγ antagonist GW9662 significantly reversed the protective effects of β-caryophyllene on APP/PS1 mice. Conclusion: These results demonstrate that the anti-inflammatory effect of the sesquiterpene β-caryophyllene involves CB2 receptor activation and the PPARγ pathway and suggest β-caryophyllene as an attractive molecule for the development of new drugs with therapeutic potential for the treatment of AD.

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Section: Discussionmentioning

confidence: 99%

β-Caryophyllene Ameliorates the Alzheimer-Like Phenotype in APP/PS1 Mice through CB2 Receptor Activation and the PPARγ Pathway

Cheng¹,

Dong²,

Li³

2014

Pharmacology

135

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“…Several studies have reported on its potential neuroprotective capabilities in various models of AD (25,26,40) as well as highlighting diseaserelated alterations that occur over time (40 -42). However, certain discrepancies also exist regarding the benefits of endocannabinoid therapeutics to AD research, with a number of studies reporting that it has no effect on AD neuropathology (43,44). Many of these inconsistencies can be explained by the use of different AD models, application of a diverse range of endocannabinoid system-modulating drugs (e.g.…”

Section: Discussionmentioning

confidence: 99%

Endocannabinoids Prevent β-Amyloid-mediated Lysosomal Destabilization in Cultured Neurons

Noonan

Tanveer

Klompas

et al. 2010

Journal of Biological Chemistry

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Neuronal cell loss underlies the pathological decline in cognition and memory associated with Alzheimer disease (AD).Recently, targeting the endocannabinoid system in AD has emerged as a promising new approach to treatment. Studies have identified neuroprotective roles for endocannabinoids against key pathological events in the AD brain, including cell death by apoptosis. Elucidation of the apoptotic pathway evoked by ␤-amyloid (A␤) is thus important for the development of therapeutic strategies that can thwart A␤ toxicity and preserve cell viability. We have previously reported that lysosomal membrane permeabilization plays a distinct role in the apoptotic pathway initiated by A␤. In the present study, we provide evidence that the endocannabinoid system can stabilize lysosomes against A␤-induced permeabilization and in turn sustain cell survival. We report that endocannabinoids stabilize lysosomes by preventing the A␤-induced up-regulation of the tumor suppressor protein, p53, and its interaction with the lysosomal membrane. We also provide evidence that intracellular cannabinoid type 1 receptors play a role in stabilizing lysosomes against A␤ toxicity and thus highlight the functionality of these receptors. Given the deleterious effect of lysosomal membrane permeabilization on cell viability, stabilization of lysosomes with endocannabinoids may represent a novel mechanism by which these lipid modulators confer neuroprotection. Alzheimer disease (AD)2 is a debilitating illness of the brain defined by the progressive deterioration of cognition and memory as a result of selective neuronal loss in the hippocampus and surrounding areas of the cerebral cortex (1). There is substantial evidence to suggest that at least a subset of neurons in the AD brain die by apoptosis (2). The principal neuropathological hallmark of the disease, ␤-amyloid peptide (A␤), has been shown to induce apoptosis in neuronal cells in vivo and in vitro (3, 4) through a variety of enzymatic pathways that include activation of caspase-3 (5), calpain (6, 7), and lysosomal cathepsins (8, 9).Recently, the lysosomal system has been implicated in AD pathogenesis (9, 10). Neurons of AD patients demonstrate alterations in the lysosomal system, including the cellular pathways that converge on it, namely endocytosis and autophagy (10, 11). Such alterations include an increase in the size and number of endosomes (10, 12), autophagosomes (13) and lysosomes (10) and an increase in the gene expression and synthesis of all classes of lysosomal hydrolases, including cathepsins (14). In addition to their role in the digestion of cellular waste, it has become clear that partial and selective lysosomal membrane permeabilization (LMP), followed by the release of lysosomal enzymes into the cytosol, can induce apoptotic cell death (15). Cathepsins D and L are among the lysosomal proteases that have been implicated in apoptosis by virtue of their ability to activate apoptotic effectors, such as mitochondrial uncoupling and caspases (16).Among the agents that are ca...

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“…Huntington's disease [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. The neuroprotective effects of cannabinoids are mediated through CB1 receptors, located in neurons, which modulate neuronal function, and CB2 receptors, mostly located in microglia, which play an important role in neuroinflammation.…”

Section: Mj Casarejos Et Al / Pk −/− /Tau Vlw Mice and Phytocannabmentioning

confidence: 99%

“…The extracts were dissolved in ethanol and mixed 1:1 to make a 20 mg/ml Sativex ® stock solution in siliconed tubes and covered in order to protect it from direct light. The Sativex ® solution was prepared as previously described [2,10,17]. The total dose of cannabinoid administered was always 4.63 mg/kg of Sativex ® (equivalent to 1.5 mg/kg of pure CBD and 1.5 mg/kg of pure THC), which is within the range of effective doses of both compounds when they were administered in pure form in other experimental models of neurodegenerative diseases [2,10,17] and in human studies [30].…”

Section: Transgenic Animals Cannabinoid Treatment and Tissue Collecmentioning

confidence: 99%

“…The Sativex ® solution was prepared as previously described [2,10,17]. The total dose of cannabinoid administered was always 4.63 mg/kg of Sativex ® (equivalent to 1.5 mg/kg of pure CBD and 1.5 mg/kg of pure THC), which is within the range of effective doses of both compounds when they were administered in pure form in other experimental models of neurodegenerative diseases [2,10,17] and in human studies [30]. This was also the effective dose in a previous study with Sativex ® -like combination of phytocannabinoids in a model of Huntington's disease [17].…”

Section: Transgenic Animals Cannabinoid Treatment and Tissue Collecmentioning

confidence: 99%

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Natural Cannabinoids Improve Dopamine Neurotransmission and Tau and Amyloid Pathology in a Mouse Model of Tauopathy

Casarejos

Perucho

Gómez

et al. 2013

JAD

109

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Abstract. Cannabinoids are neuroprotective in models of neurodegenerative dementias. Their effects are mostly mediated through CB1 and CB2 receptor-dependent modulation of excitotoxicity, inflammation, oxidative stress, and other processes. We tested the effects of Sativex ® , a mixture of 9 -tetrahydrocannabinol and cannabidiol, acting on both CB1 and CB2 receptors, in parkin-null, human tau overexpressing (PK −/− /Tau VLW ) mice, a model of complex frontotemporal dementia, parkinsonism, and lower motor neuron disease. The animals received Sativex ® , 4.63 mg/kg, ip, daily, for one month, at six months of age, at the onset of the clinical symptoms. We evaluated the effects of Sativex ® on behavior, dopamine neurotransmission, glial activation, redox state, mitochondrial activity, and deposition of abnormal proteins. PK −/− /Tau VLW mice developed the neurological deficits, but those treated with Sativex ® showed less abnormal behaviors related to stress, less auto and hetero-aggression, and less stereotypy. Sativex ® significantly reduced the intraneuronal, MAO-related free radicals produced during dopamine metabolism in the limbic system. Sativex ® also decreased gliosis in cortex and hippocampus, increased the ratio reduced/oxidized glutathione in the limbic system, reduced the levels of iNOS, and increased those of complex IV in the cerebral cortex. With regard to tau and amyloid pathology, Sativex ® reduced the deposition of both in the hippocampus and cerebral cortex of PK −/− /Tau VLW mice and increased autophagy. Sativex ® , even after a short administration in animals with present behavioral and pathological abnormalities, improves the phenotype, the oxidative stress, and the deposition of proteins in PK −/− /Tau VLW mice, a model of complex neurodegenerative disorders.

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Effect of Synthetic Cannabinoid HU210 on Memory Deficits and Neuropathology in Alzheimers Disease Mouse Model

Cited by 31 publications

References 34 publications

β-Caryophyllene Ameliorates the Alzheimer-Like Phenotype in APP/PS1 Mice through CB2 Receptor Activation and the PPARγ Pathway

β-Caryophyllene Ameliorates the Alzheimer-Like Phenotype in APP/PS1 Mice through CB2 Receptor Activation and the PPARγ Pathway

Endocannabinoids Prevent β-Amyloid-mediated Lysosomal Destabilization in Cultured Neurons

Natural Cannabinoids Improve Dopamine Neurotransmission and Tau and Amyloid Pathology in a Mouse Model of Tauopathy

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Effect of Synthetic Cannabinoid HU210 on Memory Deficits and Neuropathology in Alzheimers Disease Mouse Model

Cited by 31 publications

References 34 publications

β-Caryophyllene Ameliorates the Alzheimer-Like Phenotype in APP/PS1 Mice through CB2 Receptor Activation and the PPAR&#947; Pathway

β-Caryophyllene Ameliorates the Alzheimer-Like Phenotype in APP/PS1 Mice through CB2 Receptor Activation and the PPAR&#947; Pathway

Endocannabinoids Prevent β-Amyloid-mediated Lysosomal Destabilization in Cultured Neurons

Natural Cannabinoids Improve Dopamine Neurotransmission and Tau and Amyloid Pathology in a Mouse Model of Tauopathy

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Product

Resources

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β-Caryophyllene Ameliorates the Alzheimer-Like Phenotype in APP/PS1 Mice through CB2 Receptor Activation and the PPARγ Pathway

β-Caryophyllene Ameliorates the Alzheimer-Like Phenotype in APP/PS1 Mice through CB2 Receptor Activation and the PPARγ Pathway