scholarly journals Brain-wide structural and functional disruption in mice with oligodendrocyte specific Nf1 deletion is rescued by inhibition of NOS

2020 ◽  
Author(s):  
Jad Asleh ◽  
Ben Shofty ◽  
Nadav Cohen ◽  
Alexandra Kavushansky ◽  
Alejandro López-Juárez ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Functional Connectivity ◽  
Nitric Oxide Synthase ◽  
Motor Coordination ◽  
Motor Behavior ◽  
Neurofibromatosis Type ◽  
Brain Dysfunction ◽  
Brain White Matter ◽  
Nos Inhibitors ◽  
Oxide Synthase

AbstractNeurofibromin gene (NF1) mutation causes Neurofibromatosis type 1 (NF1), a disorder in which brain white matter deficits identified by neuroimaging are common, yet of unknown cellular etiology. In mice, Nf1 loss in adult oligodendrocyte causes myelin decompaction, and increases oligodendrocyte nitric oxide (NO) levels. Nitric oxide synthase (NOS) inhibitors rescue this pathology. Whether oligodendrocyte pathology is sufficient to affect brainwide structure and account for NF1 imaging findings is unknown. Here, we show that Nf1 gene inactivation in adult oligodendrocytes (Plp-Nf1fl/+ mice) results in a motor coordination deficit. Magnetic resonance imaging in awake mice shows that fractional anisotropy is reduced in Plp-Nf1fl/+ corpus callosum and that interhemispheric functional connectivity in motor cortex is also reduced, consistent with disrupted myelin integrity. Further, NOS-specific inhibition rescued both measures. These results demonstrate that oligodendrocyte defects account for aspects of brain dysfunction in NF1, which can be identified by neuroimaging and ameliorated by NOS inhibition.Significance statementThis study assesses the effects of myelin decompaction on motor behavior and brain-wide structural and functional connectivity, and the effect of nitric oxide synthase (NOS) inhibition by N-nitro-L-arginine methyl ester (L-NAME) on these imaging measures. We report that inducible oligodendrocyte-specific inactivation of the Nf1 gene, which causes myelin decompaction, results in reduced motor coordination. Using diffusion-based MRI we show reduced myelin integrity and using functional MRI we show reduced functional connectivity in awake passive mice. L-NAME administration results in rescue of the pathology at the mesoscopic level using imaging procedures that can be directly applied to humans to study treatment efficacy in clinical trials.

scholarly journals Brain-wide structural and functional disruption in mice with oligodendrocyte-specificNf1deletion is rescued by inhibition of nitric oxide synthase

2020 ◽  
Vol 117 (36) ◽  
pp. 22506-22513 ◽  
Author(s):  
Jad Asleh ◽  
Ben Shofty ◽  
Nadav Cohen ◽  
Alexandra Kavushansky ◽  
Alejandro López-Juárez ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Motor Coordination ◽  
Neurofibromatosis Type ◽  
Brain Dysfunction ◽  
Resonance Imaging ◽  
Brain White Matter ◽  
Nos Inhibitors ◽  
Oxide Synthase

Neurofibromin gene (NF1) mutation causes neurofibromatosis type 1 (NF1), a disorder in which brain white matter deficits identified by neuroimaging are common, yet of unknown cellular etiology. In mice,Nf1loss in adult oligodendrocytes causes myelin decompaction and increases oligodendrocyte nitric oxide (NO) levels. Nitric oxide synthase (NOS) inhibitors rescue this pathology. Whether oligodendrocyte pathology is sufficient to affect brain-wide structure and account for NF1 imaging findings is unknown. Here we show thatNf1gene inactivation in adult oligodendrocytes (Plp-Nf1fl/+mice) results in a motor coordination deficit. Magnetic resonance imaging in awake mice showed that fractional anisotropy is reduced in Plp-Nf1fl/+corpus callosum and that interhemispheric functional connectivity in the motor cortex is also reduced, consistent with disrupted myelin integrity. Furthermore, NOS-specific inhibition rescued both measures. These results suggest that oligodendrocyte defects account for aspects of brain dysfunction in NF1 that can be identified by neuroimaging and ameliorated by NOS inhibition.

A radiometric analysis of nitric oxide synthase activity in Hymenolepis diminuta

Parasitology ◽  
2000 ◽  
Vol 120 (1) ◽  
pp. 91-95 ◽  
Author(s):  
N. B. TERENINA ◽  
M. V. ONUFRIEV ◽  
N. V. GULYAEVA ◽  
A. M. LINDHOLM ◽  
M. K. S. GUSTAFSSON
Keyword(s):  
Nitric Oxide ◽  
Free Radical ◽  
Nitric Oxide Synthase ◽  
Nadph Diaphorase ◽  
Hymenolepis Diminuta ◽  
Complete Reduction ◽  
Radiometric Analysis ◽  
Nos Inhibitors ◽  
Oxide Synthase ◽  
Nitric Oxide Synthase Activity

The free radical nitric oxide (NO) is a neuronal messenger which is synthesized from L-arginine and O2 by nitric oxide synthase (NOS). In the synthesis NO and L-citrulline are produced in a stoichiometric 1[ratio ]1 relation. The activity of NOS was analysed in homogenates of the rat tapeworm Hymenolepis diminuta by measuring the formation of L-[3H]citrulline after incubation with L-[3H]arginine. The nature of NOS in H. diminuta was determined by studying the effect of 3 types of NOS inhibitors: (1) L-NAME, (2) EGTA, (3) 7-nitro-indazole. All inhibitors caused a significant but not complete reduction in the formation of L-[3H]citrulline. The results are discussed against the background of nerve cells and fibres positive for NADPH-diaphorase staining in H. diminuta.

Repeated treatment with nitric oxide synthase inhibitor attenuates learned helplessness development in rats and increases hippocampal BDNF expression

2017 ◽  
Vol 30 (3) ◽  
pp. 127-136 ◽  
Author(s):  
Laura Alves Stanquini ◽  
Caroline Biojone ◽  
Francisco Silveira Guimarães ◽  
Sâmia Regiane Joca
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Learned Helplessness ◽  
Positive Control ◽  
Repeated Treatment ◽  
Bdnf Expression ◽  
Nitric Oxide Synthase Inhibitor ◽  
Protein Levels ◽  
Nos Inhibitors ◽  
Oxide Synthase

BackgroundNitric oxide synthase (NOS) inhibitors induce antidepressant-like effects in animal models sensitive to acute drug treatment such as the forced swimming test. However, it is not yet clear if repeated treatment with these drugs is required to induce antidepressant-like effects in preclinical models.ObjectiveThe aim of this study was to test the effect induced by acute or repeated (7 days) treatment with 7-nitroindazole (7-NI), a preferential inhibitor of neuronal NOS, in rats submitted to the learned helplessness (LH) model. In addition, we aimed at investigating if 7-NI treatment would increase brain-derived neurotrophic factor (BDNF) protein levels in the hippocampus, similarly to the effect of prototype antidepressants.MethodsAnimals were submitted to a pre-test (PT) session with inescapable footshocks or habituation (no shocks) to the experimental shuttle box. Six days later they were exposed to a test with escapable footshocks. Independent groups received acute (a single injection after PT or before test) or repeated (once a day for 7 days) treatment with vehicle or 7-NI (30 mg/kg).ResultsRepeated, but not acute, treatment with 7-NI attenuated LH development. The effect was similar to repeated imipramine treatment. Moreover, in an independent experimental group, only repeated treatment with 7-NI and imipramine increased BDNF protein levels in the hippocampus.ConclusionThe results suggest the nitrergic system could be a target for the treatment of depressive-like conditions. They also indicate that, similar to the positive control imipramine, the antidepressant-like effects of NOS inhibition could involve an increase in hippocampal BDNF levels.

scholarly journals 7-Nitro indazole, a neuron-specific nitric oxide synthase inhibitor, produces amnesia in the chick.

1994 ◽  
Vol 1 (4) ◽  
pp. 213-216
Author(s):  
C Hölscher
Keyword(s):  
Nitric Oxide ◽  
Synaptic Plasticity ◽  
Nitric Oxide Synthase ◽  
Blood Vessel ◽  
Passive Avoidance ◽  
Avoidance Task ◽  
Nitric Oxide Synthase Inhibitor ◽  
Nos Inhibitors ◽  
Synthase Inhibitor ◽  
Oxide Synthase

7-Nitro indazole (7-NI), which is selective for the neuronal isoform of nitric oxide synthase (NOS), was tested in a passive avoidance task in the chick. Injection of 50 mg/kg i.p. pretraining had amnesic effects for the task when tested 30 min, 2 or 24 hr after training. Injections post-training had no effect. Because 7-NI does not inhibit the endothelial isoform of NOS, it does not affect blood vessel relaxation, as nonspecific inhibitors do. This effect on blood vessels could explain the amnestic effects produced by nonspecific NOS inhibitors. The results support the theory that NO is a neuronal transmitter that is important in processes of synaptic plasticity and learning.

scholarly journals The Role of Neuronal Nitric Oxide Synthase in Regulation of Cerebral Blood Flow in Normocapnia and Hypercapnia in Rats

1995 ◽  
Vol 15 (5) ◽  
pp. 774-778 ◽  
Author(s):  
Qiong Wang ◽  
Dale A. Pelligrino ◽  
Verna L. Baughman ◽  
Heidi M. Koenig ◽  
Ronald F. Albrecht
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Nitric Oxide Synthase ◽  
Inhibitory Action ◽  
Neuronal Nitric Oxide Synthase ◽  
Muscarinic Agonist ◽  
Doppler Flowmetry ◽  
Nos Inhibitors ◽  
Oxide Synthase

The nitric oxide synthase (NOS) inhibitors, nitro-L-arginine, its methyl ester, and N-monomethyl-L-arginine, have been shown to attenuate resting CBF and hypercapnia-induced cerebrovasodilation. Those agents nonspecifically inhibit the endothelial and neuronal NOS (eNOS and nNOS). In the present study, we used a novel nNOS inhibitor, 7-nitroindazole (7-NI) to examine the role of nNOS in CBF during normocapnia and hypercapnia in fentanyl/N2O-anesthetized rats. CBF was monitored using laser-Doppler flowmetry. Administration of 7-NI (80 mg kg−1 i.p.) reduced cortical brain NOS activity by 57%, the resting CBF by 19–27%, and the CBF response to hypercapnia by 60%. The 60% reduction was similar in magnitude to the CBF reductions observed in previous studies in which nonspecific NOS inhibitors were used. In the present study, 7-NI did not increase the MABP. Furthermore, the CBF response to oxotremorine, a blood–brain barrier permeant muscarinic agonist that induces cerebrovasodilation via endothelium-derived NO, was unaffected by 7-NI. These results confirmed that 7-NI does not influence eNOS; they also indicated that the effects of 7-NI on the resting CBF and on the CBF response to hypercapnia in this study were solely related to its inhibitory action on nNOS. The results further suggest that the NO synthesized by the action of nNOS participates in regulation of basal CBF and is the major, if not the only, category of NO contributing to the hypercapnic CBF response.

Prelimbic neuronal nitric oxide synthase inhibition exerts antidepressant-like effects independently of BDNF signalling cascades

2019 ◽  
Vol 31 (03) ◽  
pp. 143-150 ◽  
Author(s):  
Vitor Silva Pereira ◽  
Angélica C.D. Romano Suavinha ◽  
Gregers Wegener ◽  
Sâmia R.L. Joca
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Treatment Options ◽  
Nmda Antagonists ◽  
Systemic Injection ◽  
Behavioural Effects ◽  
Nos Inhibitors ◽  
Oxide Synthase ◽  
Mtor Signalling

AbstractObjectivesNMDA antagonists and nitric oxide synthase (NOS) inhibitors induce antidepressant-like effects and may represent treatment options for depression. The behavioural effects of NMDA antagonists seem to depend on Tyrosine kinase B receptor (TrkB) activation by BDNF and on mechanistic target of rapamycin (mTOR), in the medial prefrontal cortex (mPFC). However, it is unknown whether similar mechanisms are involved in the behavioural effects of NOS inhibitors. Therefore, this work aimed at determining the role of TrkB and mTOR signalling in the prelimbic area of the ventral mPFC (vmPFC-PL) in the antidepressant-like effect of NOS inhibitors.MethodsPharmacological treatment with LY235959 or ketamine (NMDA antagonists), NPA or 7-NI (NOS inhibitors), BDNF, K252a (Trk antagonist) and rapamycin (mTOR inhibitor) injected systemically or into vmPFC-PL followed by behavioural assessment.ResultsWe found that bilateral injection of BDNF into the vmPFC-PL induced an antidepressant-like effect, which was blocked by pretreatment with K252a and rapamycin. Microinjection of LY 235959 into the vmPFC-PL induced antidepressant-like effect that was suppressed by local rapamycin but not by K252a pretreatment. Microinjection of NPA induced an antidepressant-like effect insensitive to both K252a and rapamycin. Similarly, the antidepressant-like effects of a systemic injection of ketamine or 7-NI were not affected by blockade of mTOR or Trk receptors in the vmPFC-PL.ConclusionOur data support the hypothesis that NMDA blockade induces an antidepressant-like effect that requires mTOR but not Trk signalling into the vmPFC-PL. The antidepressant-like effect induced by local NOS inhibition is independent on both Trk and mTOR signalling in the vmPFC-PL.

Nitric oxide, ischaemia and brain inflammation

2007 ◽  
Vol 35 (5) ◽  
pp. 1133-1137 ◽  
Author(s):  
S. Murphy ◽  
C.L. Gibson
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Cerebral Ischaemia ◽  
Brain Inflammation ◽  
Experimental Stroke ◽  
Nitric Oxide Donors ◽  
Nos Inhibitors ◽  
Oxide Synthase ◽  
Inducible Nos

Cerebral ischaemia results in the activation of three isoforms of NOS (nitric oxide synthase) that contribute to the development of and recovery from stroke pathology. This review discusses, in particular, the role of the transcriptionally activated NOS-2 (inducible NOS) isoform and summarizes the outcomes of experimental stroke studies with regard to the therapeutic utility of nitric oxide donors and NOS inhibitors.

Timing of Administration of Dexamethasone or the Nitric Oxide Synthase Inhibitor, Nitro-l-Arginine Methyl Ester, is Critical for Effective Treatment of Ischaemia-Reperfusion Injury to Rat Skeletal Muscle

1997 ◽  
Vol 93 (2) ◽  
pp. 167-174 ◽  
Author(s):  
Baimeng Zhang ◽  
Kenneth R. Knight ◽  
Bruce Dowsing ◽  
Elizabeth Guida ◽  
Long H. Phan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Methyl Ester ◽  
Nitric Oxide Synthase ◽  
Reperfusion Injury ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Nos Inhibitors ◽  
Oxide Synthase ◽  
Inducible Nos

1. The effects of the nitric oxide synthase (NOS) inhibitors, NG-nitro-l-arginine-methyl ester (l-NAME), nitroiminoethyl-l-ornithine and S-methylisothiourea on skeletal muscle survival following 2 h of tourniquet ischaemia and 24 h of reperfusion were compared with those of the antiinflammatory steroid, dexamethasone. 2. Administration of each of the NOS inhibitors or dexamethasone 30 min before reperfusion reduced the degree of skeletal muscle necrosis 24 h after reperfusion. 3. The influence of timing of drug administration was investigated. l-NAME administered 30 min before reperfusion, at 3 h after reperfusion, but not thereafter, significantly improved muscle survival compared with saline-treated controls. Dexamethasone administered 30 min before, or at 3 or 8 h after reperfusion, but not at 16 h, significantly improved muscle survival, but neither agent had protective effects when administered before ischaemia. 4. After 8 h of reperfusion of ischaemic skeletal muscle, cell-free homogenates contained Ca2+-independent (inducible) NOS activity which was reduced in dexamethasone-treated (2.5 mg/kg) rats. Furthermore, inducible NOS mRNA levels, as detected by reverse transcriptase-PCR, were increased after 8 h of reperfusion in saline, but not in dexamethasone-treated rats. 5. These data suggest a significant deleterious effect of endogenous NO which may be restricted to the first 3 h of the reperfusion phase of ischaemia-reperfusion injury, and raise the possibility of effective treatment of incipient reperfusion injury, even after several hours of reperfusion.

Effect of nitric oxide synthase (NOS) inhibition on macro- and microcirculation in a model of rat endotoxic shock

2006 ◽  
Vol 95 (04) ◽  
pp. 720-727 ◽  
Author(s):  
Soni Pullamsetti ◽  
Daniel Maring ◽  
Hossein Ghofrani ◽  
Konstantin Mayer ◽  
Norbert Weissmann ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Septic Shock ◽  
Nitric Oxide Synthase ◽  
Rat Model ◽  
Endotoxic Shock ◽  
Nos Inhibitors ◽  
Mucosal Layer ◽  
Lactate Acidosis ◽  
Oxide Synthase

SummaryTreatment of hemodynamic instability in septic shock often demands the administration of vasopressor agents, although these may have deleterious effects on microcirculatory homeostasis. Inhibition of nitric oxide synthase (NOS) has been suggested as an alternative therapeutic approach, as NO formation may be excessively increased in sepsis. To compare the effects of epinephrine titration, non-selective NOS inhibition by L-NMMA and selective inhibition of inducible NOS (iNOS) by 1400W on hemodynamics and on the regulation of microcirculation in a rat model of endotoxic shock, we intravenously injected endotoxin (LPS) or saline to male Wist ar rats and after 2 hours randomized LPS treated rats into four different groups that received either saline, norepinephrine, L-NMMA or 1400W (n=6 per group). Three hours after LPS administration, rats presented with severe systemic arterial hypotension (64 ± 3 vs. 115 ± 4 mmHg, p<0.001), unresponsiveness to volume treatment, lactate acidosis and a marked increase in plasmatic nitrite and nitrate levels (15 ±8 vs. 263 ± 47 µM, p<0.001). Measurement of the tissue oxygenation in the ileum mucosal layer by the Erlangen micro-lightguide spectrophotometer (EMPHO) technique demonstrated marked heterogeneity of hemoglobin saturation, with appearance of low oxygenated areas. Norepinephrine, usually stabilizing blood pressure (99 ±7 vs. 67 ±4 mmHg 60 min after infusion, p<0.01), increased lactate formation (7.9± 0.2 vs. 3.7 ± 0.5 mM, p<0.001) and drastically increased low oxygenated regions in the ileum mucosal layer. L-NMMA similarly increased blood pressure (92 ±6 vs. 67 ±4 mmHg 60 min after infusion, p<0.05), but did not enhance lactate acidosis. However, some further deterioration of mucosa oxygenation was again noted. 1400W forwarded stabilization of blood pressure (88 ± 5 vs. 67 ±4 mmHg 60 min after injection, p<0.05), reduced plasmatic nitrite and nitrate levels similar to L-NMMA, without an aggravation of lactate acidosis. In addition, mucosal oxygenation did not deteriorate in response to this agent. Thereby, we conclude that in a rat model of endotoxic shock selective iNOS inhibitors are superior to non-specific NOS inhibitors and in particular to norepinephrine for the treatment of macro-and microcirculatory abnormalities in experimental septic shock.

Sign in / Sign up

Export Citation Format

Share Document