Transporter Protein-Coupled DPCPX Nanoconjugates Induce Diaphragmatic Recovery after SCI by Blocking Adenosine A1 Receptors

Minic, Zeljka; Zhang, Yanhua; Mao, Guangzhao; Goshgarian, Harry G.

doi:10.1523/jneurosci.2577-15.2016

Cited by 16 publications

(34 citation statements)

References 55 publications

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“…In general, the inspiratory drive to phrenic motoneurons is mediated by medullary neurons in the rVRG. These neurons project bilaterally (both crossed and uncrossed descending respiratory pathways) to the phrenic nuclei (21) and can be targeted by selective A1 receptor antagonists (20). In this study, adenosine A1 receptor blockade administered orally significantly enhanced MV and respiratory frequency during sleep following C2Hx injury.…”

Section: Summary Of Findingsmentioning

confidence: 57%

Sleep disordered breathing induced by cervical spinal cord injury and effect of adenosine A1 receptors modulation in rats

Sankari

Minic

Farshi

et al. 2019

Journal of Applied Physiology

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Sleep-disordered breathing (SDB) is very common after spinal cord injury (SCI). The present study was designed to evaluate the therapeutic efficacy of adenosine A1 receptor blockade (8-cyclopentyl-1,3-dipropylxanthine, DPCPX) on SDB in a rodent model of SCI. We hypothesized that SCI induced via left hemisection of the second cervical segment (C2Hx) results in SDB. We further hypothesized that blockade of adenosine A1 receptors following C2Hx would reduce the severity of SDB. In the first experiment, adult male rats underwent left C2Hx or sham (laminectomy) surgery. Unrestrained whole body plethysmography (WBP) and implanted wireless electroencephalogram (EEG) were used for assessment of breathing during spontaneous sleep and for the scoring of respiratory events at the acute (~1 wk), and chronic (~6 wk) time points following C2Hx. During the second experiment, the effect of oral administration of adenosine A1 receptor antagonist (DPCPX, 3 times a day for 4 days) on SCI induced SDB was assessed. C2Hx animals exhibited a higher apnea-hypopnea index (AHI) compared with the sham group, respectively (35.5 ± 12.6 vs. 19.1 ± 2.1 events/h, P < 0.001). AHI was elevated 6 wk following C2Hx ( week 6, 32.0 ± 5.0 vs. week 1, 42.6 ± 11.8 events/h, respectively, P = 0.12). In contrast to placebo, oral administration of DPCPX significantly decreased AHI 4 days after the treatment (159.8 ± 26.7 vs. 69.5 ± 8.9%, P < 0.05). Cervical SCI is associated with the development of SDB in spontaneously breathing rats. Adenosine A1 blockade can serve as a therapeutic target for SDB induced by SCI. NEW & NOTEWORTHY The two key novel findings of our study included that 1) induced cervical spinal cord injury results in sleep-disordered breathing in adult rats, and 2) oral therapy with an adenosine A1 receptor blockade using DPCPX is sufficient to significantly reduce apnea-hypopnea index following induced cervical spinal cord injury.

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Section: Summary Of Findingsmentioning

confidence: 57%

Sleep disordered breathing induced by cervical spinal cord injury and effect of adenosine A1 receptors modulation in rats

Sankari

Minic

Farshi

et al. 2019

Journal of Applied Physiology

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“…Dynamic light scattering (DLS) and zeta potential measurements were performed using a Malvern Nano-ZS. The same AuNP preparation was previously used in in vitro and 15 , 50 and in vivo conditions with no associated toxicity 51 , 52 .…”

Section: Methodsmentioning

confidence: 99%

Therapeutic enhancement of radiation and immunomodulation by gold nanoparticles in triple negative breast cancer

Janic

Brown

Neff

et al. 2021

Cancer Biology & Therapy

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Gold nanoparticles (AuNPs) have been shown to enhance cancer radiotherapy (RT) gain by localizing the absorption of radiation energy in the tumor while sparing surrounding normal tissue from radiation toxicity. Previously, we showed that AuNPs enhanced RT induced DNA damage and cytotoxicity in MCF7 breast cancer cells. Interestingly, we found that cancer cells exhibited a size-dependent AuNPs intracellular localization (4 nm preferentially in the cytoplasm and 14 nm in the nucleus). We extended those studies to an in vivo model and examined the AuNPs effects on RT cytotoxicity, survival and immunomodulation of tumor microenvironment (TME) in human triple negative breast cancer (TNBC) xenograft mouse model. We also explored the significance of nanoparticle size in these AuNPs’ effects. Mice treated with RT and RT plus 4 nm or 14 nm AuNPs showed a significant tumor growth delay, compared to untreated animals, while dual RT plus AuNPs treatment exhibited additive effect compared to either RT or AuNPs treatment alone. Survival log-rank test showed significant RT enhancement with 14 nm AuNP alone; however, 4 nm AuNPs did not exhibit RT enhancement. Both sizes of AuNPs enhanced RT induced immunogenic cell death (ICD) that was coupled with significant macrophage infiltration in mice pretreated with 14 nm AuNPs. These results showing significant AuNP size-dependent RT enhancement, as evident by both tumor growth delay and overall survival, reveal additional underlying immunological mechanisms and provide a platform for studying RT multimodal approaches for TNBC that may be combined with immunotherapies, enhancing their effect.

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“…T4 spinal cord transection. On day 0, the average animal weight was 369 Ϯ 21 g. The SCI surgery was performed as described previously (17,23,27,38,49), with minor modifications. Briefly, animals were anesthetized with 3% isoflurane.…”

Section: Procedures and Measurementsmentioning

confidence: 99%

Development of a decerebrate model for investigating mechanisms mediating viscero-sympathetic reflexes in the spinalized rat

Reynolds

O’Leary

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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Autonomic dysreflexia (AD) often occurs in individuals living with spinal cord injury (SCI) and is characterized by uncontrolled hypertension in response to otherwise innocuous stimuli originating below the level of the spinal lesion. Visceral stimulation is a predominant cause of AD in humans and effectively replicates the phenotype in rodent models of SCI. Direct assessment of sympathetic responses to viscerosensory stimulation in spinalized animals is challenging and requires invasive surgical procedures necessitating the use of anesthesia. However, administration of anesthesia markedly affects viscerosensory reactivity, and the effects are exacerbated following spinal cord injury (SCI). Therefore, the major goal of the present study was to develop a decerebrate rodent preparation to facilitate quantification of sympathetic responses to visceral stimulation in the spinalized rat. Such a preparation enables the confounding effect of anesthesia to be eliminated. Sprague-Dawley rats were subjected to SCI at the fourth thoracic segment. Four weeks later, renal sympathetic nerve activity (RSNA) responses to visceral stimuli were quantified in urethane/chloralose-anesthetized and decerebrate preparations. Visceral stimulation was elicited via colorectal distension (CRD) for 1 min. In the decerebrate preparation, CRD produced dose-dependent increases in mean arterial pressure (MAP) and RSNA and dose-dependent decreases in heart rate (HR). These responses were significantly greater in magnitude among decerebrate animals when compared with urethane/chloralose-anesthetized controls and were markedly attenuated by the administration of urethane/chloralose anesthesia after decerebration. We conclude that the decerebrate preparation enables high-fidelity quantification of neuronal reactivity to visceral stimulation in spinalized rats. NEW & NOTEWORTHY In animal models commonly used to study spinal cord injury, quantification of sympathetic responses is particularly challenging due to the increased susceptibility of spinal reflex circuits to the anesthetic agents generally required for experimentation. This constitutes a major limitation to understanding the mechanisms mediating regionally specific neuronal responses to visceral activation in chronically spinalized animals. In the present study, we describe a spinalized, decerebrate rodent preparation that facilitates quantification of sympathetic reactivity in response to visceral stimuli following spinal cord injury. This preparation enables reliable and reproducible quantification of viscero-sympathetic reflex responses resembling those elicited in conscious animals and may provide added utility for preclinical evaluation of neuropharmacological agents for the management of autonomic dysreflexia.

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Transporter Protein-Coupled DPCPX Nanoconjugates Induce Diaphragmatic Recovery after SCI by Blocking Adenosine A1 Receptors

Cited by 16 publications

References 55 publications

Sleep disordered breathing induced by cervical spinal cord injury and effect of adenosine A1 receptors modulation in rats

Sleep disordered breathing induced by cervical spinal cord injury and effect of adenosine A1 receptors modulation in rats

Therapeutic enhancement of radiation and immunomodulation by gold nanoparticles in triple negative breast cancer

Development of a decerebrate model for investigating mechanisms mediating viscero-sympathetic reflexes in the spinalized rat

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