Cannabinoids produce neuroprotection by reducing intracellular calcium release from ryanodine-sensitive stores

Zhuang, Shou-Yuan; Bridges, Daniel; Grigorenko, Elena; McCloud, Stephen; Boon, Andrew; Hampson, Robert E.; Deadwyler, Sam A.

doi:10.1016/j.neuropharm.2005.01.005

Cited by 92 publications

(83 citation statements)

References 68 publications

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“…This endocannabinoid-mediated neuroprotection has been reported to occur through a variety of mechanisms, including activation of prosurvival signaling pathways like inositol triphosphate (48), PI3K (49), focal adhesion kinase (50), and ERK (49 -50) as well as through inhibition of calcium currents and opening of potassium channels (51)(52)(53). The non-psychoactive component of cannabis, cannabidiol, has a number of additional characteristics that highlight the benefits of using cannabinoid-based therapeutics for the treatment of AD, such as its ability to scavenge reactive oxygen species (23), reverse Tau hyperphosphorylation (54), and reduce activation of the inflammatory transcription target, nuclear factor-B (54).…”

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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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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“…Repetitive activation of afferent fibers and synapses can induce eCB retrograde signaling through stimulation of mechanisms needed for postsynaptic eCB synthesis (3,12,(27)(28)(29)(30)(31) and by providing a synergistic presynaptic signal necessary for LTD induction (2,28,(32)(33)(34). However, it is not clear whether afferent/synaptic activation plays any role in the eCB release process.…”

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confidence: 99%

Retrograde endocannabinoid signaling at striatal synapses requires a regulated postsynaptic release step

Adermark

Lovinger

2007

Proc. Natl. Acad. Sci. U.S.A.

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Endocannabinoids (eCBs) mediate short-and long-term depression of synaptic strength by retrograde transsynaptic signaling. Previous studies have suggested that an eCB mobilization or release step in the postsynaptic neuron is involved in this retrograde signaling. However, it is not known whether this release process occurs automatically upon eCB synthesis or whether it is regulated by other synaptic factors. To address this issue, we loaded postsynaptic striatal medium spiny neurons (MSNs) with the eCBs anandamide (AEA) or 2-arachidonoylglycerol and determined the conditions necessary for presynaptic inhibition. We found that presynaptic depression of glutamatergic excitatory postsynaptic currents (EPSCs) and GABAergic inhibitory postsynaptic currents (IPSCs) induced by postsynaptic eCB loading required a certain level of afferent activation that varied between the different synaptic types. Synaptic depression at excitatory synapses was temperature-dependent and blocked by the eCB membrane transport blockers, VDM11 and UCM707, but did not require activation of metabotropic glutamate receptors, L-calcium channels, nitric oxide, voltage-activated Na ؉ channels, or intracellular calcium. Application of the CB1R antagonist, AM251, after depression was established, reversed the decrease in EPSC, but not in IPSC, amplitude. Direct activation of the CB1 receptor by WIN 55,212-2 initiated synaptic depression that was independent of afferent stimulation. These findings indicate that retrograde eCB signaling requires a postsynaptic release step involving a transporter or carrier that is activated by afferent stimulation/synaptic activation.anandamide ͉ basal ganglia ͉ synaptic plasticity ͉ CB1 receptor C hanges in synaptic strength, such as depolarization-induced suppression of excitatory (DSE) or depolarization-induced suppression of inhibitory (DSI) transmission and long-term depression (LTD), can be induced by retrograde endocannabinoid (eCB) signaling (1-3). eCB production and release can be triggered by depolarization (4-6) or neurotransmitter-induced increases in intracellular calcium concentration and after activation of G protein-coupled receptors (7, 8) or voltage-gated calcium channels (9). Postsynaptically released eCBs produce synaptic depression presumably by binding to presynaptic cannabinoid 1 receptors (CB 1 Rs) and decreasing the probability of neurotransmitter release either in a transient or sustained manner (2, 3, 10-12).The two best characterized eCBs are N-arachidonoylethanolamide [anandamide (AEA)] and 2-arachidonoylglycerol (2-AG), which are synthesized from membrane-derived lipid precursors (13,14). Diffusion and cellular uptake of both AEA and 2-AG are believed to be facilitated by an AEA transporter (AMT) (6,8,(15)(16)(17)(18), although it has been suggested that there is no need for such a transporter (19,20). AEA transport is cell-specific, unaffected by metabolic inhibitors, temperature-dependent, energy-and sodiumindependent, and believed to involve a protein carrier molecule (18,21). Inhib...

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“…In contrast, cAMP has also been shown to inhibit some forms of neurotrophin-mediated neuronal survival after serum deprivation in cultured cortical neurons (26). In addition, NMDA-induced neuronal death can be prevented through the inhibition of cAMP accumulation by cannabinoids (27). One possible explanation for the dual effects of cAMP on neuronal death is that different subtypes of adenylyl cyclases (ACs) may be involved in the process.…”

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confidence: 99%

Genetic Evidence for Adenylyl Cyclase 1 as a Target for Preventing Neuronal Excitotoxicity Mediated by N-Methyl-D-aspartate Receptors

Wang

Gong

Vadakkan

et al. 2007

Journal of Biological Chemistry

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The excessive activation of N-methyl-D-aspartate (NMDA) receptors by glutamate results in neuronal excitotoxicity. cAMP is a key second messenger and contributes to NMDA receptordependent synaptic plasticity. Adenylyl cyclases 1 (AC1) and 8 (AC8) are the two major calcium-stimulated ACs in the central nervous system. Previous studies demonstrate AC1 and AC8 play important roles in synaptic plasticity, memory, and persistent pain. However, little is known about the possible roles of these two ACs in glutamate-induced neuronal excitotoxicity. Here, we report that genetic deletion of AC1 significantly attenuated neuronal death induced by glutamate in primary cultures of cortical neurons, whereas AC8 deletion did not produce a significant effect. AC1, but not AC8, contributes to intracellular cAMP production following NMDA receptor activation by glutamate in cultured cortical neurons. AC1 is involved in the dynamic modulation of cAMP-response element-binding protein activity in neuronal excitotoxicity. To explore the possible roles of AC1 in cell death in vivo, we studied neuronal excitotoxicity induced by an intracortical injection of NMDA. Cortical lesions induced by NMDA were significantly reduced in AC1 but not in AC8 knock-out mice. Our findings provide direct evidence that AC1 plays an important role in neuronal excitotoxicity and may serve as a therapeutic target for preventing excitotoxicity in stroke and neurodegenerative diseases.Neuronal death in stroke and other neurodegenerative diseases is mainly mediated by excitotoxicity. The central role of glutamate receptors in mediating excitotoxic neuronal death has been well established (1-5). Injury to the central nervous system triggers an abnormal release of glutamate and other excitatory amino acids that contributes significantly to the neurological outcome (5-8). The released glutamate causes an excessive activation of the NMDA 2 receptors, leading to calcium overload in neurons and subsequent neuronal death (1,3,6,9). The type of cell death in neuronal excitotoxicity seems to depend on the nature of the injury. Necrosis occurs after an acute insult, whereas apoptotic cell death is involved in propagation of the secondary injury (10 -12). Neuronal apoptosis induced by activation of NMDA receptors has been postulated to underlie the loss of neurons in many central nervous system disorders (13,14). Despite the initial promise of NMDA receptor antagonists and calcium channel blockers for the reduction of excitotoxic damage, clinical trials with these agents had to be abandoned because of toxic side-effects (15-17). The intervention of signaling events, which are downstream in excitotoxic cascade, might provide new strategies for the treatment of neuronal excitotoxicity. The cAMP signaling pathway has been shown to act downstream of NMDA receptor activation in synaptic plasticity (18 -22). The effect of the cAMP signaling pathway on cell survival depends on cell type and the specific type of cellular stress and may be influenced by cross-talk with other signal...

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Cannabinoids produce neuroprotection by reducing intracellular calcium release from ryanodine-sensitive stores

Cited by 92 publications

References 68 publications

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

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

Retrograde endocannabinoid signaling at striatal synapses requires a regulated postsynaptic release step

Genetic Evidence for Adenylyl Cyclase 1 as a Target for Preventing Neuronal Excitotoxicity Mediated by N-Methyl-D-aspartate Receptors

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