Neuroprotective effects of ibudilast against tacrolimus induced neurotoxicity

Zhang, Wei; Matsukane, Ryosuke; Egashira, Nobuaki; Tsuchiya, Yosuke; Fu, Rao; Yamamoto, Seigo; Hirota, Tomoyoshi; Ieiri, Ichiro

doi:10.1016/j.taap.2022.116112

Cited by 4 publications

(4 citation statements)

References 36 publications

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“…76 Similarly, neurological symptoms (i.e., seizures or tremors) increased as the intracerebral concentration of tacrolimus was raised over pharmacological threshold in rats. 77,78 In comparison to healthy animals, rats administered tacrolimus had a significant decrease of brain-derived neurotrophic factor (BDNF) in the dentate gyrus and CA3 region of the hippocampus. 79 Since BDNF is critical for the development and survival of neurons, as well as neuroplasticity, 80,81 reduction in BDNF levels can disrupt these critical processes with potential for cognitive dysfunction.…”

Section: Calcineurin Inhibitors (Cnis)mentioning

confidence: 99%

“…Administration of tacrolimus was found to reduce oxygen consumption and adenosine triphosphate synthesis within rat forebrain mitochondria 76 . Similarly, neurological symptoms (i.e., seizures or tremors) increased as the intracerebral concentration of tacrolimus was raised over pharmacological threshold in rats 77,78 . In comparison to healthy animals, rats administered tacrolimus had a significant decrease of brain‐derived neurotrophic factor (BDNF) in the dentate gyrus and CA3 region of the hippocampus 79 .…”

Section: Impact Of Long‐term Immunosuppression On the Brainmentioning

confidence: 99%

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Understanding the impact of pediatric kidney transplantation on cognition: A review of the literature

Lullmann,

van der Plas,

Harshman

2023

Pediatric Transplantation

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BackgroundChronic kidney disease (CKD) is a relatively rare childhood disease that is associated with a wide array of medical comorbidities. Roughly half of all pediatric patients acquire CKD due to congenital anomalies of the kidneys and urinary tract, and of those with congenital disease, 50% will progress to end‐stage kidney disease (ESKD) necessitating a kidney transplantation. The medical sequelae of advanced CKD/ESKD improve dramatically following successful kidney transplantation; however, the impact of kidney transplantation on neurocognition in children is less clear. It is generally thought that cognition improves following kidney transplantation; however, our knowledge on this topic is limited by the sparsity of high‐quality data in the context of the relative rarity of pediatric CKD/ESKD.MethodWe conducted a narrative review to gauge the scope of the literature, using the PubMed database and the following keywords: cognition, kidney, brain, pediatric, neurocognition, intelligence, executive function, transplant, immunosuppression, and neuroimaging.ResultsThere are few published longitudinal studies, and existing work often includes wide heterogeneity in age at transplant, variable dialysis exposure/duration prior to transplant, and unaccounted cofounders which persist following transplantation, including socio‐economic status. Furthermore, the impact of long‐term maintenance immunosuppression on the brain and cognitive function of pediatric kidney transplant (KT) recipients remains unknown.ConclusionIn this educational review, we highlight what is known on the topic of neurocognition and neuroimaging in the pediatric KT population.

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Section: Calcineurin Inhibitors (Cnis)mentioning

confidence: 99%

Section: Impact Of Long‐term Immunosuppression On the Brainmentioning

confidence: 99%

Understanding the impact of pediatric kidney transplantation on cognition: A review of the literature

Lullmann,

van der Plas,

Harshman

2023

Pediatric Transplantation

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“…Ibudilast is currently approved in Japan for the treatment of post-stroke dizziness and asthma (Cho et al, 2010; Rolan, Hutchinson, & Johnson, 2009). Recently, ibudilast was found to have neuroprotective effects in a variety of neurological disorders (Egashira et al, 2021; Fujita et al, 2018; Zhang et al, 2022). It is in clinical trials in the United States for evaluation as a neuroprotective agent in amyotrophic lateral sclerosis (Oskarsson et al, 2021) and multiple sclerosis (Bermel et al, 2021; Fox et al, 2018; MediciNova, Health, Disorders, Stroke, & Society, 2013; MediciNova & System, 2014; Oskarsson et al, 2021) as well as in drug addiction (Grodin et al, 2022) and pain (Egashira et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Ibudilast Protects Retinal Bipolar Cells from Excitotoxic Retinal Damage and Activates the mTOR Pathway

Hamadmad,

Heisler-Taylor,

Goswami

et al. 2024

Preprint

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Ibudilast, an inhibitor of macrophage migration inhibitory factor (MIF) and phosphodiesterase (PDE), has been recently shown to have neuroprotective effects in a variety of neurologic diseases. We utilize a chick excitotoxic retinal damage model to investigate ibudilast's potential to protect retinal neurons. Using single cell RNA-sequencing (scRNA-seq), we find that MIF, putative MIF receptors CD74 and CD44, and several PDEs are upregulated in different retinal cells during damage. Intravitreal ibudilast is well tolerated in the eye and causes no evidence of toxicity. Ibudilast effectively protects neurons in the inner nuclear layer from NMDA-induced cell death, restores retinal layer thickness on spectral domain optical coherence tomography, and preserves retinal neuron function, particularly for the ON bipolar cells, as assessed by electroretinography. PDE inhibition seems essential for ibudilast's neuroprotection, as AV1013, the analogue that lacks PDE inhibitor activity, is ineffective. scRNA-seq analysis reveals upregulation of multiple signaling pathways, including mTOR, in damaged Müller glia (MG) with ibudilast treatment compared to AV1013. Components of mTORC1 and mTORC2 are upregulated in both bipolar cells and MG with ibudilast. The mTOR inhibitor rapamycin blocked accumulation of pS6 but did not reduce TUNEL positive dying cells. Additionally, through ligand-receptor interaction analysis, crosstalk between bipolar cells and MG may be important for neuroprotection. We have identified several paracrine signaling pathways that are known to contribute to cell survival and neuroprotection and might play essential roles in ibudilast function. These findings highlight ibudilast's potential to protect inner retinal neurons during damage and show promise for future clinical translation.

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“…Apart from its bronchodilator properties, several pharmacological activities have been attributed to ibudilast, including the vasodilating, anti-thrombotic and anti-leukotriene properties [ 23 ]. The emerging preclinical evidence has demonstrated that ibudilast may also exert significant anti-neuroinflammatory effects for a wide range of neurological disorders, including chronic cerebral hypoperfusion [ 24 ], peripheral and central neuropathic pain [ 25 ], opioid withdrawal [ 26 ], human immunodeficiency virus-1 (HIV-1)-associated neurocognitive disorders (HAND) [ 27 ], cerebral aneurysms [ 28 ], transient cerebral ischemia [ 29 ], ischemic brain injury [ 30 ], post-stroke dizziness [ 18 , 19 ], oxaliplatin-induced tactile allodynia and cognitive impairment [ 31 ], tacrolimus-induced neurotoxicity [ 32 ] and cocaine use disorder [ 33 ], among others. Neuroinflammation and microglia activation are shared mechanisms underlying the pathophysiology of these conditions [ 34 ], thus also highlighting the potential of ibudilast to mitigate aberrant inflammatory responses in the case of neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

Emerging Potential of the Phosphodiesterase (PDE) Inhibitor Ibudilast for Neurodegenerative Diseases: An Update on Preclinical and Clinical Evidence

2022

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Neurodegenerative diseases constitute a broad range of central nervous system disorders, characterized by neuronal degeneration. Alzheimer’s disease, Parkinson’s disease, amyolotrophic lateral sclerosis (ALS), and progressive forms of multiple sclerosis (MS) are some of the most frequent neurodegenerative diseases. Despite their diversity, these diseases share some common pathophysiological mechanisms: the abnormal aggregation of disease-related misfolded proteins, autophagosome–lysosome pathway dysregulation, impaired ubiquitin–proteasome system, oxidative damage, mitochondrial dysfunction and excessive neuroinflammation. There is still no effective drug that could halt the progression of neurodegenerative diseases, and the current treatments are mainly symptomatic. In this regard, the development of novel multi-target pharmaceutical approaches presents an attractive therapeutic strategy. Ibudilast, an anti-inflammatory drug firstly developed as an asthma treatment, is a cyclic nucleotide phosphodiesterases (PDEs) inhibitor, which mainly acts by increasing the amount of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), while downregulating the pro-inflammatory factors, such as tumor necrosis factor-α (TNF-α), macrophage migration inhibitory factor (MIF) and Toll-like receptor 4 (TLR-4). The preclinical evidence shows that ibudilast may act neuroprotectively in neurodegenerative diseases, by suppressing neuroinflammation, inhibiting apoptosis, regulating the mitochondrial function and by affecting the ubiquitin–proteasome and autophagosome–lysosome pathways, as well as by attenuating oxidative stress. The clinical trials in ALS and progressive MS also show some promising results. Herein, we aim to provide an update on the emerging preclinical and clinical evidence on the therapeutic potential of ibudilast in these disorders, discuss the potential challenges and suggest the future directions.

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Neuroprotective effects of ibudilast against tacrolimus induced neurotoxicity

Cited by 4 publications

References 36 publications

Understanding the impact of pediatric kidney transplantation on cognition: A review of the literature

Understanding the impact of pediatric kidney transplantation on cognition: A review of the literature

Ibudilast Protects Retinal Bipolar Cells from Excitotoxic Retinal Damage and Activates the mTOR Pathway

Emerging Potential of the Phosphodiesterase (PDE) Inhibitor Ibudilast for Neurodegenerative Diseases: An Update on Preclinical and Clinical Evidence

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