Inosine attenuates 3-nitropropionic acid-induced Huntington's disease-like symptoms in rats via the activation of the A2AR/BDNF/TrKB/ERK/CREB signaling pathway

El-Shamarka, Marwa El-Sayed; El-Sahar, Ayman E.; Saad, Marina; Assaf, Naglaa; Sayed, Rabab H.

doi:10.1016/j.lfs.2022.120569

Cited by 22 publications

(17 citation statements)

References 59 publications

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“…The latter can be attributed to two reasons. First, the binding of inosine to A 2A R (a Gs protein‐coupled receptor) results in an increase of cAMP levels (El‐Shamarka et al, 2022; Welihinda et al, 2016). Subsequently, the increased cAMP concentration activates the protein kinase A (PKA), leading to the phosphorylation and activation of AMPK (Moon et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Besides, inosine has been shown to enhance the axonal growth of undamaged neurons (Doyle et al, 2018) and to increase both neuronal survival and neurite outgrowth after damage of the central nervous system (Muto et al, 2014). Experimentally, inosine has been reported to induce significant enhancement in motor function in neurological diseases models, including traumatic brain injury (Dachir et al, 2014), stroke (Moore et al, 2016), Huntington's disease (El‐Shamarka et al, 2022), and PD (Schwarzschild et al, 2014). Inosine has also been shown to exert a protective effect against the oxidative stress‐induced death of dopaminergic cells in a PD cellular model (Cipriani et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, inosine can activate AMPK through its action on A 2A R (a Gs protein‐coupled receptor). The A 2A R occupation resulted in increasing intracellular level of cyclic adenosine monophosphate (cAMP) (El‐Shamarka et al, 2022; Welihinda et al, 2016), which can subsequently increase the phosphorylation and activation of AMPK (Omar et al, 2009). The aim of the present study was to investigate the neuroprotective effects of inosine against rotenone‐induced PD in rats via the activation of AMPK‐mediated autophagy.…”

Section: Introductionmentioning

confidence: 99%

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Inosine attenuates rotenone‐induced Parkinson's disease in rats by alleviating the imbalance between autophagy and apoptosis

El‐Latif

Rabie

Sayed

et al. 2023

Drug Development Research

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Growing evidence points to impaired autophagy as one of the major factors implicated in the pathophysiology of Parkinson's disease (PD). Autophagy is a downstream target of adenosine monophosphate‐activated protein kinase (AMPK). Inosine has already demonstrated a neuroprotective effect against neuronal loss in neurodegenerative diseases, mainly due its anti‐inflammatory and antioxidant properties. We, herein, aimed at investigating the neuroprotective effects of inosine against rotenone‐induced PD in rats and to focus on the activation of AMPK‐mediated autophagy. Inosine successfully increased p‐AMPK/AMPK ratio in PD rats and improved their motor performance and muscular co‐ordination (assessed by rotarod, open field, and grip strength tests, as well as by manual gait analysis). Furthermore, inosine was able to mitigate the rotenone‐induced histopathological alterations and to restore the tyrosine hydroxylase immunoreactivity in PD rats' substantia nigra. Inosine‐induced AMPK activation resulted in an autophagy enhancement, as demonstrated by the increased striatal Unc‐S1‐like kinase1 and beclin‐1 expression, and also by the increment light chain 3II to light chain 3I ratio, along with the decline in striatal mammalian target of rapamycin and p62 protein expressions. The inosine‐induced stimulation of AMPK also attenuated neuronal apoptosis and promoted antioxidant activity. Unsurprisingly, these neuroprotective effects were antagonized by a preadministration of dorsomorphin (an AMPK inhibitor). In conclusion, inosine exerted neuroprotective effects against the rotenone‐induced neuronal loss via an AMPK activation and through the restoration of the imbalance between autophagy and apoptosis. These findings support potential application of inosine in PD treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inosine attenuates rotenone‐induced Parkinson's disease in rats by alleviating the imbalance between autophagy and apoptosis

El‐Latif

Rabie

Sayed

et al. 2023

Drug Development Research

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“…In particular, it has been shown that inosine reduced 3-nitropropionic acid (3-NP)-induced HD-like symptoms in rats, at least in part, by activating the A2AR/BDNF/TrKB/ERK/CREB signaling pathway [ 74 ].…”

Section: Discussionmentioning

confidence: 99%

Inosine in Neurodegenerative Diseases: From the Bench to the Bedside

2022

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Neurodegenerative diseases, such as Alzheimer′s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), currently represent major unmet medical needs. Therefore, novel therapeutic strategies are needed in order to improve patients’ quality of life and prognosis. Since oxidative stress can be strongly involved in neurodegenerative diseases, the potential use of inosine, known for its antioxidant properties, in this context deserves particular attention. The protective action of inosine treatment could be mediated by its metabolite urate. Here, we review the current preclinical and clinical studies investigating the use of inosine in AD, PD, ALS, and MS. The most important properties of inosine seem to be its antioxidant action and its ability to raise urate levels and to increase energetic resources by improving ATP availability. Inosine appears to be generally safe and well tolerated; however, the possible formation of kidney stones should be monitored, and data on its effectiveness should be further explored since, so far, they have been controversial. Overall, inosine could be a promising potential strategy in the management of neurodegenerative diseases, and additional studies are needed in order to further investigate its safety and efficacy and its use as a complementary therapy along with other approved drugs.

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“…Recent studies have shown neuroprotective and neuromodulatory functions of inosine in a variety of neurological and psychiatric diseases ( Nascimento et al, 2021 ). Inosine treatment ameliorated 3-nitropropionic acid (3-NP)-induced neurotoxicity and boosted brain-derived neurotrophic factor (BDNF) levels, p-cAMP response element-binding protein (CREB) expression, and glutathione content ( El-Shamarka et al, 2022 ). In addition, metformin-mediated amelioration of methamphetamine withdrawal syndrome is at least partly mediated through altered bacterial composition and metabolite changes such as abundance of Rikenellaceae and inosine ( Yang et al, 2022 ).…”

Section: Inosine and Other Diseasesmentioning

confidence: 99%

Inosine: A bioactive metabolite with multimodal actions in human diseases

Kim

2022

Front. Pharmacol.

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The nucleoside inosine is an essential metabolite for purine biosynthesis and degradation; it also acts as a bioactive molecule that regulates RNA editing, metabolic enzyme activity, and signaling pathways. As a result, inosine is emerging as a highly versatile bioactive compound and second messenger of signal transduction in cells with diverse functional abilities in different pathological states. Gut microbiota remodeling is closely associated with human disease pathogenesis and responses to dietary and medical supplementation. Recent studies have revealed a critical link between inosine and gut microbiota impacting anti-tumor, anti-inflammatory, and antimicrobial responses in a context-dependent manner. In this review, we summarize the latest progress in our understanding of the mechanistic function of inosine, to unravel its immunomodulatory actions in pathological settings such as cancer, infection, inflammation, and cardiovascular and neurological diseases. We also highlight the role of gut microbiota in connection with inosine metabolism in different pathophysiological conditions. A more thorough understanding of the mechanistic roles of inosine and how it regulates disease pathologies will pave the way for future development of therapeutic and preventive modalities for various human diseases.

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Inosine attenuates 3-nitropropionic acid-induced Huntington's disease-like symptoms in rats via the activation of the A2AR/BDNF/TrKB/ERK/CREB signaling pathway

Cited by 22 publications

References 59 publications

Inosine attenuates rotenone‐induced Parkinson's disease in rats by alleviating the imbalance between autophagy and apoptosis

Inosine attenuates rotenone‐induced Parkinson's disease in rats by alleviating the imbalance between autophagy and apoptosis

Inosine in Neurodegenerative Diseases: From the Bench to the Bedside

Inosine: A bioactive metabolite with multimodal actions in human diseases

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