Neuropathological Effects of Chemotherapeutic Drugs

Umfress, Alan; Speed, Haley E.; Tan, Chunfeng; Ramezani, Saleh; Birnbaum, Shari G.; Brekken, Rolf A.; Sun, Xiankai; Plattner, Florian; Powell, Craig M.; Bibb, James A.

doi:10.1021/acschemneuro.1c00338

Cited by 12 publications

(12 citation statements)

References 81 publications

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“…Wang & L. I. Xiang-Yao) show that local infusion of cisplatin into the ACC increases the paw withdrawal threshold and extends the thermal withdrawal latency. As a result of the systemic application of cisplatin leading to chemotherapy-induced polyneuropathy [56], the development of novel Casp3 activators is a future requirement.…”

Section: Nerve Injury Damages Ltd Induction Which Contributes To Peri...mentioning

confidence: 99%

Targeting long‐term depression of excitatory synaptic transmission for the treatment of neuropathic pain

Wang

Lian

et al. 2021

The FEBS Journal

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Injury or disease in the somatosensory nervous system may cause broad molecular changes and lead to neuropathic pain. Excitatory synaptic transmission in somatosensory pathways conveys the somatosensory information from the peripheral to the central nervous system. Long-term effects of excitatory synaptic transmission on the pain pathway contribute to neuropathic pain hypersensitivity. Synaptic strength is dynamically regulated and undergoes bidirectional changes, manifested by two primary forms of synaptic plasticity, long-term potentiation and long-term depression (LTD), which are mediated by insertion and endocytosis of amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), respectively. Molecular mechanisms of LTP have been extensively studied; on the other hand, the role of AMPAR endocytosis in the pain-related synaptic enhancement is less well known. Recent research in the anterior cingulate cortex reveals that loss of LTD contributes to the maintenance of neuropathic pain, which provides the novel perspective of the mechanism of LTD also being critical for maintaining neuropathic pain. More importantly, exploring the molecular mechanism of LTD may help with the development of novel analgesic strategies to manage neuropathic pain.

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Section: Nerve Injury Damages Ltd Induction Which Contributes To Peri...mentioning

confidence: 99%

Targeting long‐term depression of excitatory synaptic transmission for the treatment of neuropathic pain

Wang

Lian

et al. 2021

The FEBS Journal

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“…Immunoblotting was performed as previously described ( Umfress et al, 2021 ). Mouse brains were rapidly dissected in an ice-cold solution of 50 mM NaF/PBS.…”

Section: Methodsmentioning

confidence: 99%

Systemic Administration of a Brain Permeable Cdk5 Inhibitor Alters Neurobehavior

et al. 2022

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Cyclin-dependent kinase 5 (Cdk5) is a crucial regulator of neuronal signal transduction. Cdk5 activity is implicated in various neuropsychiatric and neurodegenerative conditions such as stress, anxiety, depression, addiction, Alzheimer’s disease, and Parkinson’s disease. While constitutive Cdk5 knockout is perinatally lethal, conditional knockout mice display resilience to stress-induction, enhanced cognition, neuroprotection from stroke and head trauma, and ameliorated neurodegeneration. Thus, Cdk5 represents a prime target for treatment in a spectrum of neurological and neuropsychiatric conditions. While intracranial infusions or treatment of acutely dissected brain tissue with compounds that inhibit Cdk5 have allowed the study of kinase function and corroborated conditional knockout findings, potent brain-penetrant systemically deliverable Cdk5 inhibitors are extremely limited, and no Cdk5 inhibitor has been approved to treat any neuropsychiatric or degenerative diseases to date. Here, we screened aminopyrazole-based analogs as potential Cdk5 inhibitors and identified a novel analog, 25–106, as a uniquely brain-penetrant anti-Cdk5 drug. We characterize the pharmacokinetic and dynamic responses of 25–106 in mice and functionally validate the effects of Cdk5 inhibition on open field and tail-suspension behaviors. Altogether, 25–106 represents a promising preclinical Cdk5 inhibitor that can be systemically administered with significant potential as a neurological/neuropsychiatric therapeutic.

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“…Immunoblotting was performed as previously described (Umfress et al, 2021). Briefly, rat brains were rapidly dissected and submerged in a 4˚C solution of PBS/50 mM NaF.…”

Section: Immunoblottingmentioning

confidence: 99%

“…Histology was performed as described (Umfress et al, 2021). Briefly, rats were transcardially perfused with 1X PBS/50 mM NaF followed by 10% formalin fixation.…”

Section: Histologymentioning

confidence: 99%

Characterization and Preclinical Treatment of Rotational Force-Induced Brain Injury

Umfress

Chakraborti

Devi

et al. 2022

Preprint

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Millions of traumatic brain injuries (TBIs) occur annually. TBIs commonly result from falls, traffic accidents, and sports-related injuries, all of which involve rotational acceleration/deceleration of the brain. During these injuries, the brain endures a multitude of primary insults including compression of brain tissue, damaged vasculature, and diffuse axonal injury. All of these deleterious effects can contribute to secondary brain ischemia, cellular death, and neuroinflammation that progress for weeks to months after injury and impede neurological recovery. While the linear effects of head trauma have been extensively modeled, less is known about how rotational injuries mediate neuronal damage following injury. Here, we developed a new model of rotational head trauma in rodents and extensively characterized the pathological, behavioral, and electrophysiological effects of rotational TBI (rTBI). We identify aberrant cyclin dependent kinase 5 (Cdk5) activity as a principal mediator of rTBI and show pharmacological inhibition of Cdk5 reduces the cognitive and pathological consequences of injury. Finally, we utilize Cdk5-enriched phosphoproteomics to uncover potential downstream mediators of rTBI. These studies contribute meaningfully to our understanding of the mechanisms of rTBI and how they may be effectively treated.

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Neuropathological Effects of Chemotherapeutic Drugs

Cited by 12 publications

References 81 publications

Targeting long‐term depression of excitatory synaptic transmission for the treatment of neuropathic pain

Targeting long‐term depression of excitatory synaptic transmission for the treatment of neuropathic pain

Systemic Administration of a Brain Permeable Cdk5 Inhibitor Alters Neurobehavior

Characterization and Preclinical Treatment of Rotational Force-Induced Brain Injury

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