Characterization of Neuroprotective Effects of Biphalin, an Opioid Receptor Agonist, in a Model of Focal Brain Ischemia

Li, Yang; Shah, Kaushik; Wang, Hezhen; Karamyan, Vardan T.; Abbruscato, Thomas J.

doi:10.1124/jpet.111.184127

Cited by 41 publications

(41 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In an in vivo model of ischemia, biphalin significantly decreased edema and infarct ratios in mouse transient and permanent middle cerebral artery occlusion models. Biphalin administration also decreased neurodegeneration in hippocampal, cortical, and striatal brain tissue after ischemia [9]. In vitro studies in hippocampal organotypic cultures demonstrated that biphalin possesses a much higher neuroprotective effect than morphine.…”

Section: Resultsmentioning

confidence: 98%

“…However, it should be considered that these "non-specific" distributions and interactions may have a biological function; furthermore, these activities may be physiologically important. Recent neurobiological studies have provided evidence for the neuroprotective effects of opioids [1,9]. A partial reversal of these effects using opioid antagonists indicated that, in addition to specific opioid receptor involvement, non-receptor effects should also be examined.…”

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

The non-opioid receptor, antioxidant properties of morphine and the opioid peptide analog biphalin

et al. 2015

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 98%

The non-opioid receptor, antioxidant properties of morphine and the opioid peptide analog biphalin

et al. 2015

View full text Add to dashboard Cite

“…Since past investigations have reported biphalin to play a central role in reducing neuronal cellular edema by modulating ion transporter function and expression (Yang et al, 2011a), and reduce edema in both hippocampal slices subjected to OGD and reduce cellular edema in primary neurons subjected to OGD (Yang et al, 2011b), the first aim of this study was to detect the anti-edematous efficacy of biphalin in vivo and compare it to classical, OR-selective agonists. In addition, we compared the effects of these drugs on infarction size and neurological deficit after stroke.…”

Section: Introductionmentioning

confidence: 99%

In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtype-selective opioid receptor agonists for stroke treatment

Islam²,

Karamyan³

et al. 2015

Brain Research

Self Cite

View full text Add to dashboard Cite

To meet the challenge of identification of new treatments for stroke, this study was designed to evaluate a potent, nonselective opioid receptor (OR) agonist, biphalin, in comparison to subtype selective OR agonists, as a potential neuroprotective drug candidate using in vitro and in vivo models of ischemic stroke. Our in vitro approach included mouse primary neuronal cells that were challenged with glutamate and hypoxic/aglycemic (H/A) conditions. We observed that 10 nM biphalin, exerted a statistically significant neuroprotective effect after glutamate challenge, compared to all selective opioid agonists, according to lactate dehydrogenase (LDH) and 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays. Moreover, 10 nM biphalin provided superior neuroprotection after H/A-reoxygenation compared to selective opioid agonists in all cases. Our in vitro investigations were supported by in vivo studies which indicate that the nonselective opioid agonist, biphalin, achieves enhanced neuroprotective potency compared to any of the selective opioid agonists, evidenced by reduced edema and infarct ratios. Reduction of edema and infarction was accompanied by neurological improvement of the animals in two independent behavioral tests. Collectively these data strongly suggest that concurrent agonist stimulation of mu, kappa and delta ORs with biphalin is neuroprotective and superior to neuroprotection by activation of any single OR subtype.

show abstract

“…Interestingly, extensive motor training following stroke increases neuroprotective isoforms of PKC in a time-dependent manner leading to decreased BBB permeability [15]. Likewise δ opioid agonists increase the translocation of the neuroprotective isoform PKC ε from the cytosol to nuclear membrane following stroke, thus providing protection for neurons [16]. …”

Section: Introductionmentioning

confidence: 99%

Common Mechanisms of Alzheimer's Disease and Ischemic Stroke: The Role of Protein Kinase C in the Progression of Age-Related Neurodegeneration

Lucke‐Wold

Turner

Logsdon

et al. 2014

JAD

View full text Add to dashboard Cite

Ischemic stroke and Alzheimer’s disease (AD), despite being distinct disease entities, share numerous pathophysiological mechanisms such as those mediated by inflammation, immune exhaustion, and neurovascular unit compromise. An important shared mechanistic link is acute and chronic changes in protein kinase C (PKC) activity. PKC isoforms have widespread functions important for memory, blood-brain barrier maintenance, and injury repair that change as the body ages. Disease states accelerate PKC functional modifications. Mutated forms of PKC can contribute to neurodegeneration and cognitive decline. In some cases the PKC isoforms are still functional but are not successfully translocated to appropriate locations within the cell. The deficits in proper PKC translocation worsen stroke outcome and amyloid-β toxicity. Cross talk between the innate immune system and PKC pathways contribute to the vascular status within the aging brain. Unfortunately, comorbidities such as diabetes, obesity, and hypertension disrupt normal communication between the two systems. The focus of this review is to highlight what is known about PKC function, how isoforms of PKC change with age, and what additional alterations are consequences of stroke and AD. The goal is to highlight future therapeutic targets that can be applied to both the treatment and prevention of neurologic disease. Although the pathology of ischemic stroke and AD are different, the similarity in PKC responses warrants further investigation, especially as PKC-dependent events may serve as an important connection linking age-related brain injury.

show abstract

Characterization of Neuroprotective Effects of Biphalin, an Opioid Receptor Agonist, in a Model of Focal Brain Ischemia

Cited by 41 publications

References 39 publications

The non-opioid receptor, antioxidant properties of morphine and the opioid peptide analog biphalin

The non-opioid receptor, antioxidant properties of morphine and the opioid peptide analog biphalin

In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtype-selective opioid receptor agonists for stroke treatment

Common Mechanisms of Alzheimer's Disease and Ischemic Stroke: The Role of Protein Kinase C in the Progression of Age-Related Neurodegeneration

Contact Info

Product

Resources

About