Although it is well established that cyclic adenosine monophosphate (cAMP) signalling via cAMP-dependent protein kinase (PKA)within neurons plays an important role in depression and antidepressant treatment, the importance of several newly discovered targets that function independently from PKA, such as exchange protein activated by cAMP (Epac), remains unexplored in this regard. In this study we used a cAMP analogue that inhibits PKA but not Epac (Rp-8-Br-cAMP), to explore the modifying actions of these two targets on immobility in the forced swim test (FST) and cerebellar cAMP response element binding protein (CREB) phosphorylation in rats. In addition, we assessed central cAMP and cGMP levels and investigated the involvement of cGMP-dependent protein kinase (PKG) on any observed effects by using a selective PKG inhibitor (Rp-8-Br-PET-cGMPS).Interestingly, Rp-8-Br-cAMPS strongly reduced immobility in the FST and induced an increase in the phosphorylation of CREB in the cerebellum, effects that were unaltered by the co-administration of Rp-8-Br-PET-cGMPS. Furthermore, Rp-8-Br-cAMPS increased the accumulation of cAMP and cGMP in the hippocampus, frontal cortex and cerebellum of these rats. Together, these results suggest that in addition to activating PKA, elevated cAMP may also stimulate other targets that mediate antidepressant activity. According to the pharmacodynamic profile of Rp-8-Br-cAMPS and taking into consideration what has recently been discovered regarding the cAMP signalling system, a likely candidate is the guanine nucleotide exchange factor, Epac.

1999-12-01·Neuroscience Letters4区 · 医学

Inhibition of spinal protein kinase C reduces nerve injury-induced tactile allodynia in neuropathic rats

4区 · 医学

Article

作者: Xiao-Ying Hua ; Tony L Yaksh ; Ping Chen

We investigated the effects of inhibiting spinal protein kinases including PKC, PKA and PKG on tactile allodynia in rats with a unilateral tight ligation on L5/L6 spinal nerves (Chung model). The intrathecal (IT) delivery of GF109203X, a PKC inhibitor, produced a potent and long lasting anti-allodynic effect. The effect was dose-dependent and stereospecific. Bisindolymaleimide V, an inactive homologue of GF, had no effect. Additionally, two other PKC inhibitors, PKC19-31 and chelerythrine, displayed significant anti-allodynic action. Spinal PKA, but not PKG, is likely involved in Chung tactile allodynia, since H89 (a PKA inhibitor) showed anti-allodynic activity, while KT5823 (a PKG inhibitor) had only a minor effect. These data emphasize that spinal PKC plays an important role in nerve injury-induced tactile allodynia. Other protein kinases such as PKA may also contribute to this phenomenon.

Frontiers in Neurology3区 · 医学

PKG Movement Recording System Use Shows Promise in Routine Clinical Care of Patients With Parkinson's Disease

3区 · 医学

ArticleOA

作者: Bronstein, Jeffrey M ; Joshi, Maya ; Alcazar, Jaclyn ; Keener, A ; Hermanowicz, Neal ; Yang, Diane D ; Joshi, Rajeshree

Parkinson's disease (PD) is a debilitating, neurodegenerative disorder that affects nearly one million people. It's hallmark signs and symptoms include slow movements, rigidity, tremor, and unstable posture. Additionally, non-motor symptoms such as sleeplessness, depression, cognitive impairment, impulse control behaviors (ICB) have been reported. Today, treatment regimens to modify disease progression do not exist and as such, treatment is focused on symptom relief. Additionally, physicians are challenged to base their diagnoses and treatment plans on unreliable self-reported symptoms, even when used in conjunction to validated assessments such as the Unified Parkinson's Disease Rating Scale (UPDRS) and clinical exams. Wearable technology may provide clinicians objective measures of motor problems to supplement current subjective methods. Global Kinetics Corporation (GKC) has developed a watch-device called the Personal KinetiGraph (PKG) that records movements and provides patients medication dosing reminders. A separate clinician-use report supplies longitudinal motor and event data. The PKG was FDA-cleared in September 2016. We studied 63 PD patients during 85 routine care visits in 2 US academic institutions, evaluating the clinical utility of the PKG. Patients wore a PKG for 6 continuous days before their visit. Next, PKG data was uploaded to produce a report. In clinic, physicians discussed PD symptoms with patients and conducted a motor examination prior to reviewing the PKG report and comparing it to their initial assessments. Lastly, patient, caregiver and physician satisfaction surveys were conducted by each user. Across all visits when patients did not report bradykinesia or dyskinesia, the PKG reported these symptoms (50 and 33% of the time, respectively). The PKG provided insights for treatment plans in 50 (79%) patients across 71 (84%) visits. Physicians found improved patient dialogue in 50 (59%) visits, improved ability to assess treatment impact in 32 (38%) visits, and improved motor assessment in 28 (33%) visits. Patients stated in 82% of responses that they agreed or strongly agreed in PKG training, usability, performance, and satisfaction. In 39% of responses, they also reported a very valuable impact on their care. PKG use in 63 PD patients within our clinical practice showed clinically relevant utility in many areas.

项与 PKG activators(Merck) 相关的新闻（医药）

2024-09-20

·Endpoints

Novo axes Phase 2 of Forma-acquired drug in myelodysplastic syndromes

Novo Nordisk has ended one of the multiple trials testing the lead oral drug from its $1.1 billion Forma Therapeutics buyout , according to an update to the US federal trials database this week. The Danish drug giant terminated a Phase 2 trial of etavopivat for anemia in adults with various forms of myelodysplastic syndromes, or MDS, according to an update to the US clinical trials site on Thursday. In patients with MDS, red blood cells don’t mature or become healthy ones, and the cancer can progress into leukemia. The drug is still being tested in mid – and late-stage trials for patients with sickle cell disease and thalassemia. Novo made the decision after a “futility assessment concluded low likelihood of the trial showing meaningful patient benefit,” according to an update to the Fortitude trial registry. “This decision was not taken lightly and reflects a judgement of low likelihood that the Fortitude trial would generate benefit for patients with MDS,” a Novo spokesperson said in an emailed statement to Endpoints News . MDS wasn’t highlighted in Novo’s deal announcement in fall 2022, but it was nonetheless another patient population that the pharmaceutical company had hoped to treat with the selective pyruvate kinase-R activator. Patients with sickle cell disease and thalassemia are the main populations for which Novo is developing the once-daily medicine. “We remain confident in etavopivat’s promise and are committed to its continued development in sickle cell disease (SCD) and thalassemia,” the spokesperson said. “The termination of the Fortitude trial does not diminish our belief in etavopivat’s potential to make a significant impact on patients’ lives.” Novo highlighted the asset’s potential in MDS in its annual report in January. Agios Pharmaceuticals is also testing a PK activator, dubbed tebapivat, for MDS-associated anemia. Agios’ more advanced PK activator, mitapivat, is approved for adult PK deficiency and marketed as Pyrukynd. Bristol Myers Squibb’s Reblozyl is indicated for MDS-related anemia. Since the acquisition, Novo has offloaded some of the pipeline at Forma, a drug developer that had touted “ the science of giving a damn. ” It sold a preclinical cancer candidate to Debiopharm and a Phase 1 prostate cancer drug to Pathos AI .

上市批准并购临床1期临床2期

100 项与 PKG activators(Merck) 相关的药物交易

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