Postoperative cognitive dysfunction is made persistent with morphine treatment in aged rats

Muscat, Stephanie; Deems, Nicholas P.; D’Angelo, Heather; Kitt, Meagan M.; Grace, Peter M.; Andersen, Nathan D.; Silverman, Shaelyn N.; Rice, Kenner C.; Watkins, Linda R.; Maier, Steven F.; Barrientos, Ruth M.

doi:10.1016/j.neurobiolaging.2020.11.008

Cited by 34 publications

(21 citation statements)

References 69 publications

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“…One study, however, found higher levels of cytokines, such as IL-10 and TNFa, in the serum of animals treated with Bup compared to the control animals 63 , suggesting a potentially unique role of Bup on neuroin ammation as compared to other opioids. Another study recently found increased expression of IL-1b in the hippocampus of aged rats treated with morphine 64 weeks following surgical procedures, indicating that there might also be neuroin ammatory changes at later time points, which this study would not have captured. These possibilities will need to be further assessed at later time points following diffuse TBI, when neuroin ammatory responses are more robust 39,56 .…”

Section: Discussionmentioning

confidence: 63%

Buprenorphine Alters Microglia and Astrocytes Acutely Following Diffuse Traumatic Brain Injury.

Ryu

Stone

Lee³

et al. 2021

Preprint

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Background: Traumatic brain injury (TBI) is a common phenomenon, accounting for significant cost and adverse health effects. While there is information about focal pathologies following TBI, knowledge of more diffuse processes is lacking, particularly regarding how analgesics affect this pathology. As buprenorphine is the most commonly used analgesic in experimental TBI models, this study investigated the acute effects of the opioid analgesic buprenorphine (Bup-SR-Lab) on diffuse neuronal/glial pathology, neuroinflammation, cell damage, and systemic physiology. Methods: We utilized a model of central fluid percussion injury (CFPI) in adult male rats treated with a single subcutaneous bolus of Bup-SR-Lab or saline 15min post-injury. Microscopic assessments were performed at 1 day post-injury. Cell impermeable dextran was infused intraventricularly prior to sacrifice to assess neuronal membrane disruption. Axonal injury was assessed by investigating labeling of the anterogradely transported amyloid precursor protein. Neuroinflammation was assessed by analyzing Iba-1+ microglial and GFAP+ astrocyte histological/morphological features as well as cytokine levels in both regions of interest (ROIs). Myelin pathology was assessed by evaluating the expression of myelin basic protein (MBP) and the propensity of MBP+ myelin debris. Results: Acute physiologic data showed no difference between groups except for reduction in weight loss following cFPI in Bup treated animals compared to saline. There were no discernable differences in axonal injury or membrane disruption between treatment groups. Cytokine levels were consistent between Bup and saline treated animals, however, microglia and astrocytes revealed region specific histological changes at 1d following Bup treatment. Myelin integrity and overall MBP expression showed no differences between Bup and saline treated animals, but there were significant regional differences in MBP expression between the cortex and thalamus.Conclusions: These data suggest effects of Bup treatment on weight following CFPI and potential regional specificity of Bup-associated microglial and astrocyte alterations, but very little change in other acute pathology at 1-day post-injury. Overall, this preliminary study indicates that use of Bup-SR-Lab in preclinical work does have effects on acute glial pathology, however, longer term studies will be needed to assess potential effects of Bup treatment on more chronic pathological progressions.

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Section: Discussionmentioning

confidence: 63%

Buprenorphine Alters Microglia and Astrocytes Acutely Following Diffuse Traumatic Brain Injury.

Ryu

Stone

Lee³

et al. 2021

Preprint

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“…Remyelination helps restore the neuronal function and prevents neurodegeneration ( Del Giovane and Ragnini-Wilson, 2018 ). PSD95, BDNF and SNAP25 are the synaptic plasticity-related proteins that closely related to neuronal function, learning and memory ( Qiu et al, 2020 ; Jia et al, 2021 ; Muscat et al, 2021 ). Protein-protein interaction analysis results indicated that there were co-expression relationships between MBP, PSD95, BDNF and SNAP25 ( Figure 6A ).…”

Section: Resultsmentioning

confidence: 99%

“…The expression level of SNAP25 in the hippocampus of rats with vascular dementia is closely related to the severity of disease ( Ren et al, 2018 ). Furthermore, the significant down-regulated expression level of PSD95 in hippocampus of PND aged rats suggesting that impaired synaptic structure and/or function might have a key role in this persistent defect ( Muscat et al, 2021 ). BDNF is the most abundant neurotrophic factor in the body, mainly expressed in the cortex and hippocampus.…”

Section: Discussionmentioning

confidence: 99%

Clemastine Ameliorates Perioperative Neurocognitive Disorder in Aged Mice Caused by Anesthesia and Surgery

Zhang

Zhou

et al. 2021

Front. Pharmacol.

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Perioperative neurocognitive disorder (PND) leads to progressive deterioration of cognitive function, especially in aged patients. Demyelination is closely associated with cognitive dysfunction. However, the relationship between PND and demyelination remains unclear. Here we showed that demyelination was related to the pathogenesis of PND. Clemastine, an antihistamine with potency in remyelination, was predicted to have a potential therapeutic effect on PND by next-generation sequencing and bioinformatics in our previous study. In the present study, it was given at 10 mg/kg per day for 2 weeks to evaluate the effects on PND in aged mice. We found that clemastine ameliorated PND and reduced the expression levels of inflammatory factors such as tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β). Further investigation suggested clemastine increased the expression of oligodendrocyte transcription factor 2 (OLIG2) and myelin basic protein (MBP) to enhance remyelination by inhibiting the overactivation of the WNT/β-catenin pathway. At the same time, the expression of post-synaptic density protein 95 (PSD95, or DLG4), brain-derived neurotrophic factor (BDNF), synaptosomal-associated protein 25 (SNAP25) and neuronal nuclei (NEUN) were also improved. Our results suggested that clemastine might be a therapy for PND caused by anesthetic and surgical factors in aged patients.

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“…1 ). Preclinically, we and others have demonstrated that an array of surgeries, such as various abdominal, orthopedic, and cardiac surgeries, result in exaggerated neuroinflammation and, consequentially, cognitive impairment, in aged but not young adult rodents [ 46–51 ]. Similarly, peripheral infections, including E. coli , influenza A, and human immunodeficiency virus (HIV), have been shown been associated with memory impairments disproportionately in aged systems as compared to young adult ones.…”

Section: Introductionmentioning

confidence: 99%

The Perfect Cytokine Storm: How Peripheral Immune Challenges Impact Brain Plasticity & Memory Function in Aging

Muscat

Barrientos

2021

BPL

Self Cite

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Precipitous declines in cognitive function can occur in older individuals following a variety of peripheral immune insults, such as surgery, infection, injury, and unhealthy diet. Aging is associated with numerous changes to the immune system that shed some light on why this abrupt cognitive deterioration may occur. Normally, peripheral-to-brain immune signaling is tightly regulated and advantageous; communication between the two systems is bi-directional, via either humoral or neural routes. Following an immune challenge, production, secretion, and translocation of cytokines into the brain is critical to the development of adaptive sickness behaviors. However, aging is normally associated with neuroinflammatory priming, notably microglial sensitization. Microglia are the brain’s innate immune cells and become sensitized with advanced age, such that upon immune stimulation they will mount more exaggerated neuroimmune responses. The resultant elevation of pro-inflammatory cytokine expression, namely IL-1β, has profound effects on synaptic plasticity and, consequentially, cognition. In this review, we (1) investigate the processes which lead to aberrantly elevated inflammatory cytokine expression in the aged brain and (2) examine the impact of the pro-inflammatory cytokine IL-1β on brain plasticity mechanisms, including its effects on BDNF and AMPA and NMDA receptor-mediated long-term potentiation.

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Postoperative cognitive dysfunction is made persistent with morphine treatment in aged rats

Cited by 34 publications

References 69 publications

Buprenorphine Alters Microglia and Astrocytes Acutely Following Diffuse Traumatic Brain Injury.

Buprenorphine Alters Microglia and Astrocytes Acutely Following Diffuse Traumatic Brain Injury.

Clemastine Ameliorates Perioperative Neurocognitive Disorder in Aged Mice Caused by Anesthesia and Surgery

The Perfect Cytokine Storm: How Peripheral Immune Challenges Impact Brain Plasticity & Memory Function in Aging

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