Distinct regulation of nNOS and iNOS by CB2 receptor in remote delayed neurodegeneration

Oddi, Sergio; Latini, Laura; Viscomi, Maria Teresa; Bisicchia, Elisa; Molinari, Marco; Maccarrone, Mauro

doi:10.1007/s00109-011-0846-z

Cited by 39 publications

(45 citation statements)

References 34 publications

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“…Repeated administration of the CB2 receptor agonist JWH-105 reduces the inflammatory response to MDMA and provides partial protection against 5-hydroxytriptamine neurotoxicity [60]. Stimulation of CB2 signaling elicits a series of molecular and cellular events that attenuates delayed neurodegeneration [34]. Future studies should be performed in order to evaluate the potential role of CB2 receptors in both neurons and microglia in THC-induced neuroprotection.…”

Section: Discussionmentioning

confidence: 99%

“…Mice lacking the nNOS gene are significantly more resistant to N-Methyl-D-aspartate- (NMDA) or METH-induced neurotoxicity and 3-nitrotyrosine production than wild-type mice [31], [32]. Notably, nNOS plays also an important role in cannabinoid-induced neurogenesis and neuroprotection through both the CB1 and CB2 receptors [33], [34]. Few studies have reported that Δ9-THC prevents 3,4-methylenedioxymethamphetamine(MDMA) neurotoxicity [35], [36]; yet, no study has thus far investigated the effects of cannabinoids in METH-induced neurotoxicity.…”

Section: Introductionmentioning

confidence: 99%

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Δ9-Tetrahydrocannabinol Prevents Methamphetamine-Induced Neurotoxicity

et al. 2014

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Methamphetamine (METH) is a potent psychostimulant with neurotoxic properties. Heavy use increases the activation of neuronal nitric oxide synthase (nNOS), production of peroxynitrites, microglia stimulation, and induces hyperthermia and anorectic effects. Most METH recreational users also consume cannabis. Preclinical studies have shown that natural (Δ9-tetrahydrocannabinol, Δ9-THC) and synthetic cannabinoid CB1 and CB2 receptor agonists exert neuroprotective effects on different models of cerebral damage. Here, we investigated the neuroprotective effect of Δ9-THC on METH-induced neurotoxicity by examining its ability to reduce astrocyte activation and nNOS overexpression in selected brain areas. Rats exposed to a METH neurotoxic regimen (4×10 mg/kg, 2 hours apart) were pre- or post-treated with Δ9-THC (1 or 3 mg/kg) and sacrificed 3 days after the last METH administration. Semi-quantitative immunohistochemistry was performed using antibodies against nNOS and Glial Fibrillary Acidic Protein (GFAP). Results showed that, as compared to corresponding controls (i) METH-induced nNOS overexpression in the caudate-putamen (CPu) was significantly attenuated by pre- and post-treatment with both doses of Δ9-THC (−19% and −28% for 1 mg/kg pre- and post-treated animals; −25% and −21% for 3 mg/kg pre- and post-treated animals); (ii) METH-induced GFAP-immunoreactivity (IR) was significantly reduced in the CPu by post-treatment with 1 mg/kg Δ9-THC1 (−50%) and by pre-treatment with 3 mg/kg Δ9-THC (−53%); (iii) METH-induced GFAP-IR was significantly decreased in the prefrontal cortex (PFC) by pre- and post-treatment with both doses of Δ9-THC (−34% and −47% for 1 mg/kg pre- and post-treated animals; −37% and −29% for 3 mg/kg pre- and post-treated animals). The cannabinoid CB1 receptor antagonist SR141716A attenuated METH-induced nNOS overexpression in the CPu, but failed to counteract the Δ9-THC-mediated reduction of METH-induced GFAP-IR both in the PFC and CPu. Our results indicate that Δ9-THC reduces METH-induced brain damage via inhibition of nNOS expression and astrocyte activation through CB1-dependent and independent mechanisms, respectively.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Δ9-Tetrahydrocannabinol Prevents Methamphetamine-Induced Neurotoxicity

et al. 2014

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“…A form of RNS, nitric oxide (NO), production is also increased following TBI [2,61-64] and participates in neurodegenerative cascades [2,27,65]. NO can be derived from different NO-synthase among which is endothelial NOS (eNOS) [66].…”

Section: Introductionmentioning

confidence: 99%

A time course of NADPH-oxidase up-regulation and endothelial nitric oxide synthase activation in the hippocampus following neurotrauma

Ansari

Roberts

Scheff

2014

Free Radical Biology and Medicine

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Nicotinamide adenine dinucleotide phosphate oxidase (NADPH-oxidase; NOX) is a complex enzyme responsible for increased levels of reactive oxygen species (ROS), superoxide (O2.−). NOX derived O2.− is a key player in oxidative stress and inflammation mediated multiple secondary injury cascades (SIC) following traumatic brain injury (TBI). The O2.− reacts with nitric oxide (NO), produces various reactive nitrogen species (RNS), and contributes to apoptotic cell death. Following a unilateral cortical contusion, young adult rats were killed at various times post injury (1, 3, 6, 12, 24, 48, 72, and 96 h). Fresh tissue from the hippocampus was analyzed for NOX activity, and level of O2.−. In addition we evaluated the translocation of cytosolic NOX proteins (p67Phox, p47Phox and p40Phox) to the membrane, along with total NO and the activation (phosphorylation) of endothelial nitric oxide synthase (p-eNOS). Results show that both enzymes and levels of O2.− and NO have time dependent injury effects in the hippocampus. Translocation of cytosolic NOX proteins into membrane, NOX activity and O2.− were also increased in a time dependent fashion. Both, NOX activity and O2.− were increased at 6 h. Levels of p-eNOS increased within 1 h, with significant elevation of NO at 12 h post TBI. Levels of NO failed to show a significant association with p-eNOS, but did associate with O2.−. NOX up-regulation strongly associated with both the levels of O2.− and also total NO. The initial 12 hours post TBI are very important as a possible window of opportunity to interrupt SIC. It may be important to selectively target the translocation of cytosolic subunits for the modulation of NOX function.

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“…The ECS is a ubiquitous ligand-directed signalling system, which has been implicated in regulating a wide range of physiological processes and pathologies, including energy homoeostasis, cardiovascular disease, cancer, and neurodegeneration (Di Marzo and Petrocellis, 2006; Mukhopadhyay et al, 2010b; Oddi et al, 2012). Two key lipid-derived molecules that act as endogenous ligands for this system are anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG)—commonly referred to as endocannabinoids.…”

Section: The Ecsmentioning

confidence: 99%

“…In accord with this, inhibition of LPS-induced NO • release in macrophages by WIN 55,212-2 was shown to be mediated through stimulation of CB2R (Ross et al, 2000). Interestingly, independent work by Oddi et al (2012) revealed that daily treatment of rats with the CB2R agonist JWH-015 for one week markedly attenuated hemicerebellectomy induction of iNOS expression and associated oxidative/nitrosative stress, concomitant with improved neurological outcome measures. Intriguingly, Oddi et al (2012) further demonstrated that JWH-015 treatment increased nNOS expression and activity in axotomized neurons, and the observed neuroprotection conveyed by CB2R activity was abrogated in response to pharmacological inhibition of nNOS.…”

Section: Modulation Of Nitrergic Signalling By the Ecsmentioning

confidence: 99%

The endocannabinoid system: ‘NO’ longer anonymous in the control of nitrergic signalling?

Lipina

Hundal

2017

Journal of Molecular Cell Biology

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The endocannabinoid system (ECS) is a key cellular signalling system that has been implicated in the regulation of diverse cellular functions. Importantly, growing evidence suggests that the biological actions of the ECS may, in part, be mediated through its ability to regulate the production and/or release of nitric oxide, a ubiquitous bioactive molecule, which functions as a versatile signalling intermediate. Herein, we review and discuss evidence pertaining to ECS-mediated regulation of nitric oxide production, as well as the involvement of reactive nitrogen species in regulating ECS-induced signal transduction by highlighting emerging work supporting nitrergic modulation of ECS function. Importantly, the studies outlined reveal that interactions between the ECS and nitrergic signalling systems can be both stimulatory and inhibitory in nature, depending on cellular context. Moreover, such crosstalk may act to maintain proper cell function, whereas abnormalities in either system can undermine cellular homoeostasis and contribute to various pathologies associated with their dysregulation. Consequently, future studies targeting these signalling systems may provide new insights into the potential role of the ECS–nitric oxide signalling axis in disease development and/or lead to the identification of novel therapeutic targets for the treatment of nitrosative stress-related neurological, cardiovascular, and metabolic disorders.

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Distinct regulation of nNOS and iNOS by CB2 receptor in remote delayed neurodegeneration

Cited by 39 publications

References 34 publications

Δ9-Tetrahydrocannabinol Prevents Methamphetamine-Induced Neurotoxicity

Δ9-Tetrahydrocannabinol Prevents Methamphetamine-Induced Neurotoxicity

A time course of NADPH-oxidase up-regulation and endothelial nitric oxide synthase activation in the hippocampus following neurotrauma

The endocannabinoid system: ‘NO’ longer anonymous in the control of nitrergic signalling?

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