Involvement of metabotropic glutamate receptors in Gi- and Gs-dependent modulation of adenylate cyclase activity induced by a novel cognition enhancer NS-105 in rat brain

Oka, Michiko; Itoh, Yoshinori; Shimidzu, Takako; Ukai, Yojiro; Yoshikuni, Yoshiaki; Kimura, Kiyoshi

doi:10.1016/s0006-8993(97)00064-4

Cited by 13 publications

(3 citation statements)

References 33 publications

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“…66 Our group’s research in ADHD is focused on characterizing genetic variants that disrupt a specific pathway (the glutamatergic pathway) involving neurotransmission in the brain. We recently identified a small molecule compound, NFC-1, which previously underwent extensive clinical testing 67 and was shown to have stimulatory activity towards mGluR pathways, 68 –70 producing notable psychoactive effects in animal models. 71,72 The drug was originally developed in the late 1980s for treating dementia-related cognitive impairment but was eventually abandoned during phase III trials in dementia.…”

Section: Futurementioning

confidence: 99%

Attention-Deficit Hyperactivity Disorder and Pharmacotherapy—Past, Present, and Future: A Review of the Changing Landscape of Drug Therapy

Connolly

Glessner

Kao

et al. 2015

Ther Innov Regul Sci

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Attention deficit hyperactivity disorder (ADHD) is the most common neurobiological disorder in children, with a prevalence of ~6-7% 1,2 that has remained stable for decades 2 . The social and economic burden associated with patients 3 , families, and broader systems (healthcare/educational) is substantial, with the annual economic impact of ADHD exceed $30 billion in the US alone 4 . Efficacy of pharmacotherapy in treating ADHD symptoms has generally been considerable with at least ¾ of individuals benefitting from pharmacotherapy, typically in the form of stimulants 5 . In this review, we begin by briefly reviewing the history of pharmacotherapy in relation to ADHD, before focusing (primarily) on the state-of-the-field on themes such as biophysiology, pharmacokinetics, and pharmacogenomics. We conclude with a summary of emerging clinical and research studies, particularly the potential role for precision therapy in matching ADHD patients and drug types. KeywordsADHD; pharmacotherapy; pharmacology; drug; medication; adverse events PASTThe most common and effective medications are methylphenidates and amphetamines. Atomoxetine and the a-adrenergic agonists are also widely-used, while tricyclics such as modafinil and Wellbutrin are less common and typically less effective 6 .First synthesized in 1887, amphetamine (alpha-methylphenethylamine) was not studied clinically until 1927, initially as an artificial replacement for epinephrine 7 . For several years,

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Section: Futurementioning

confidence: 99%

Attention-Deficit Hyperactivity Disorder and Pharmacotherapy—Past, Present, and Future: A Review of the Changing Landscape of Drug Therapy

Connolly

Glessner

Kao

et al. 2015

Ther Innov Regul Sci

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“…Interestingly, in close temporal convergence, we discovered the downregulation of the "Cellular response to cAMP" within the first 4 weeks after SCI before recovering at chronic stages. Given the temporal overlap between the upregulation of glutamate and adenosine receptor cascade with the downregulation of the cAMP response, we suggest the implication of glutamate and ATP leakage in cAMP decay after SCI through Gi protein activation linked to metabotropic glutamate receptors or adenosine receptors [ 67 , 68 ]; however, we note the need for further experimental validation to fully explore and validate this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

NPC transplantation rescues sci-driven cAMP/EPAC2 alterations, leading to neuroprotection and microglial modulation

Martínez-Rojas

Giraldo

Grillo-Risco

et al. 2022

Cell. Mol. Life Sci.

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Neural progenitor cell (NPC) transplantation represents a promising treatment strategy for spinal cord injury (SCI); however, the underlying therapeutic mechanisms remain incompletely understood. We demonstrate that severe spinal contusion in adult rats causes transcriptional dysregulation, which persists from early subacute to chronic stages of SCI and affects nearly 20,000 genes in total tissue extracts. Functional analysis of this dysregulated transcriptome reveals the significant downregulation of cAMP signalling components immediately after SCI, involving genes such as EPAC2 (exchange protein directly activated by cAMP), PKA, BDNF, and CAMKK2. The ectopic transplantation of spinal cord-derived NPCs at acute or subacute stages of SCI induces a significant transcriptional impact in spinal tissue, as evidenced by the normalized expression of a large proportion of SCI-affected genes. The transcriptional modulation pattern driven by NPC transplantation includes the rescued expression of cAMP signalling genes, including EPAC2. We also explore how the sustained in vivo inhibition of EPAC2 downstream signalling via the intrathecal administration of ESI-05 for 1 week impacts therapeutic mechanisms involved in the NPC-mediated treatment of SCI. NPC transplantation in SCI rats in the presence and absence of ESI-05 administration prompts increased rostral cAMP levels; however, NPC and ESI-05 treated animals exhibit a significant reduction in EPAC2 mRNA levels compared to animals receiving only NPCs treatment. Compared with transplanted animals, NPCs + ESI-05 treatment increases the scar area (as shown by GFAP staining), polarizes microglia into an inflammatory phenotype, and increases the magnitude of the gap between NeuN + cells across the lesion. Overall, our results indicate that the NPC-associated therapeutic mechanisms in the context of SCI involve the cAMP pathway, which reduces inflammation and provides a more neuropermissive environment through an EPAC2-dependent mechanism. Graphical abstract

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“…NFC-1 (fasoracetam monohydrate) is a small synthetic molecule and a metabotropic glutamate receptor activator, which has previously undergone extensive Phase I-III clinical trials in humans for vascular dementia 14 . Preclinical studies demonstrated that that NFC-1 affects mGluRs 15 – 17 , acetylcholine release and uptake 18 and GABAb, but not adrenoceptors, serotonergic or dopaminergic receptors 19 , potentially reversing learning and memory deficits caused by dysfunction of central cholinergic neurons in a variety of models 15 , 16 . It may have the potential to restore normal glutamatergic activity in ADHD patients with glutamatergic hypofunction due to mutations in mGluR network genes.…”

Section: Introductionmentioning

confidence: 99%

Fasoracetam in adolescents with ADHD and glutamatergic gene network variants disrupting mGluR neurotransmitter signaling

et al. 2018

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The glutamatergic neurotransmitter system may play an important role in attention-deficit hyperactivity disorder (ADHD). This 5-week, open-label, single-blind, placebo-controlled study reports the safety, pharmacokinetics and responsiveness of the metabotropic glutamate receptor (mGluR) activator fasoracetam (NFC-1), in 30 adolescents, age 12–17 years with ADHD, harboring mutations in mGluR network genes. Mutation status was double-blinded. A single-dose pharmacokinetic profiling from 50–800 mg was followed by a single-blind placebo at week 1 and subsequent symptom-driven dose advancement up to 400 mg BID for 4 weeks. NFC-1 treatment resulted in significant improvement. Mean Clinical Global Impressions-Improvement (CGI-I) and Severity (CGI-S) scores were, respectively, 3.79 at baseline vs. 2.33 at week 5 (P < 0.001) and 4.83 at baseline vs. 3.86 at week 5 (P < 0.001). Parental Vanderbilt scores showed significant improvement for subjects with mGluR Tier 1 variants (P < 0.035). There were no differences in the incidence of adverse events between placebo week and weeks on active drug. The trial is registered at https://clinicaltrials.gov/ct2/show/study/NCT02286817.

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Involvement of metabotropic glutamate receptors in Gi- and Gs-dependent modulation of adenylate cyclase activity induced by a novel cognition enhancer NS-105 in rat brain

Cited by 13 publications

References 33 publications

Attention-Deficit Hyperactivity Disorder and Pharmacotherapy—Past, Present, and Future: A Review of the Changing Landscape of Drug Therapy

Attention-Deficit Hyperactivity Disorder and Pharmacotherapy—Past, Present, and Future: A Review of the Changing Landscape of Drug Therapy

NPC transplantation rescues sci-driven cAMP/EPAC2 alterations, leading to neuroprotection and microglial modulation

Fasoracetam in adolescents with ADHD and glutamatergic gene network variants disrupting mGluR neurotransmitter signaling

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