Heat Shock Protein 72 Overexpression Prevents Early Postoperative Memory Decline after Orthopedic Surgery under General Anesthesia in Mice

Vizcaychipi, Marcela P.; Xu, Lijun; Barreto, George E.; Ma, Daqing; Maze, Mervyn; Giffard, Rona G.

doi:10.1097/aln.0b013e31820ad3ce

Cited by 46 publications

(43 citation statements)

References 47 publications

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“…Furthermore, PF3845 increased the expression of the anti-apoptotic protein, Bcl-2, and the anti-oxidant proteins, Hsp70/72. Increased expression of these proteins was found to provide neuroprotection after brain injury (Oddi et al, 2012) and to prevent surgery-induced memory decline (Vizcaychipi et al, 2011). Consistent with those findings, a recent report demonstrated that AEA enhances the expression of Hsp72, which contributes to the protection against ischemic injury (Li et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

The fatty acid amide hydrolase inhibitor PF-3845 promotes neuronal survival, attenuates inflammation and improves functional recovery in mice with traumatic brain injury

Tchantchou

Tucker

et al. 2014

Neuropharmacology

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Traumatic brain injury (TBI) is the leading cause of death in young adults in the United States, but there is still no effective agent for treatment. N-arachidonoylethanolamine (anandamide, AEA) is a major endocannabinoid in the brain. Its increase after brain injury is believed to be protective. However, the compensatory role of AEA is transient due to its rapid hydrolysis by the fatty acid amide hydrolase (FAAH). Thus, inhibition of FAAH can boost the endogenous levels of AEA and prolong its protective effect. Using a TBI mouse model, we found that post-injury chronic treatment with PF3845, a selective and potent FAAH inhibitor, reversed TBI-induced impairments in fine motor movement, hippocampus dependent working memory and anxiety-like behavior. Treatment with PF3845 inactivated FAAH activity and enhanced the AEA levels in the brain. It reduced neurodegeneration in the dentate gyrus, and up-regulated the expression of Bcl-2 and Hsp70/72 in both cortex and hippocampus. PF3845 also suppressed the increased production of amyloid precursor protein, prevented dendritic loss and restored the levels of synaptophysin in the ipsilateral dentate gyrus. Furthermore, PF3845 suppressed the expression of inducible nitric oxide synthase and cyclooxygenase-2 and enhanced the expression of arginase-1 post-TBI, suggesting a shift of microglia/macrophages from M1 to M2 phenotype. The effects of PF3845 on TBI-induced behavioral deficits and neurodegeneration were mediated by activation of cannabinoid type 1 and 2 receptors and might be attributable to the phosphorylation of ERK1/2 and AKT. These results suggest that selective inhibition of FAAH is likely to be beneficial for TBI treatment.

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Section: Discussionmentioning

confidence: 99%

The fatty acid amide hydrolase inhibitor PF-3845 promotes neuronal survival, attenuates inflammation and improves functional recovery in mice with traumatic brain injury

Tchantchou

Tucker

et al. 2014

Neuropharmacology

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“…6–9,27,28 The expression of cognitive decline is due to neuroinflammation that produces a constellation of symptoms, referred to as “sickness behavior,” which is thought to protect the traumatized organism from further injury and to facilitate the healing process. 29 This is a short-lived process in which neuroinflammation is curtailed by feedback mechanisms that involve both neural (especially the parasympathetic nervous system), as well as humoral (including oxygenated and nitrogenated lipid) factors.…”

Section: Discussionmentioning

confidence: 99%

Surgery Results in Exaggerated and Persistent Cognitive Decline in a Rat Model of the Metabolic Syndrome

Feng¹,

Degos²,

Koch³

et al. 2013

Anesthesiology

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Background Postoperative cognitive decline can be reproduced in animal models. In a well-validated rat model of the Metabolic Syndrome, we sought to investigate whether surgery induced a more severe and persistent form of cognitive decline similar to that noted in preliminary clinical studies. Methods In rats that had been selectively bred for low and high exercise endurance, the low capacity runners (LCR) exhibited features of Metabolic Syndrome (obesity, dyslipidemia, insulin resistance, and hypertension). Tibial fracture surgery was performed under isoflurane anesthesia in LCR and high capacity runner (HCR) rats and cognitive function was assessed postoperatively in a trace-fear conditioning paradigm and Morris Water Maze; non-operated rats were exposed to anesthesia and analgesia (sham). Group sizes were n = 6. Results On postoperative D7, LCR rats had shorter freezing times than postoperative HCR rats. Five months postoperatively, LCR rats had a flatter learning trajectory and took longer to locate the submerged platform than postoperative HCR rats; dwell-time in the target quadrant in a probe trial was shorter in the postoperative LCR compared to HCR rats. LCR and HCR sham rats did not differ in any test. Conclusion Postoperatively, LCR rats diverged from HCR rats exhibiting a greater decline in memory, acutely, with persistent learning and memory decline, remotely; this could not be attributed to changes in locomotor or swimming performance. This Metabolic Syndrome animal model of surgery-induced cognitive decline corroborates, with high fidelity, preliminary findings of postoperative cognitive dysfunction in Metabolic Syndrome patients.

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“…This test consists of a training phase prior to surgery and a test phase 1, 3, and 7 days after surgery [24]. …”

Section: Methodsmentioning

confidence: 99%

Activation of cannabinoid receptor type 2 attenuates surgery-induced cognitive impairment in mice through anti-inflammatory activity

Sun

Dong

et al. 2017

J Neuroinflammation

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BackgroundNeuroinflammation plays a major role in postoperative cognitive dysfunction (POCD). Accumulated evidence indicates that cannabinoid receptor type 2 (CB2R) can mediate anti-inflammatory and immunomodulatory effects in part by controlling microglial activity. However, the impact of CB2R on postoperative cognition has not been investigated. We hypothesized that CB2R is involved in surgery-induced cognitive impairment in adult mice.MethodsAdult C57BL/6 mice were subjected to intramedullary fixation surgery for tibial fracture under isoflurane anesthesia and CB2R agonist (JWH133) or CB2R antagonist (AM630) treatment. The mice were trained 24 h prior to surgery using a fear conditioning protocol and assessed in a novel context on postoperative days 1, 3, and 7 to evaluate cognitive function. Open-field testing was performed to evaluate the locomotor activity of the mice. The expression levels of IL-1β, TNF-α, MCP-1, and CB2R in the hippocampus and prefrontal cortex were assessed by Western blotting; the expression of microglial marker CD11b in the CA1 area of the hippocampus and medial prefrontal cortex was assessed by immunostaining.ResultsThe mice displayed no changes in locomotor activity after surgery and drug treatments. The mice exhibited impaired hippocampal-dependent memory accompanied by an increased expression of proinflammatory factors in the hippocampus and prefrontal cortex 1, 3, and 7 days after surgery, while hippocampal-independent memory remained unaffected at the same time points. JWH133 treatment attenuated surgery-induced memory loss, while AM630 treatment aggravated surgery-induced memory loss, paralleled by a decreased or increased expression of proinflammatory factors in the hippocampus and prefrontal cortex. The expression of CB2R in the hippocampus and prefrontal cortex was upregulated following surgery; however, it was downregulated by postoperative treatment with JWH133. Similarly, the expression of CD11b in the CA1 area of the hippocampus and medial prefrontal cortex was upregulated following surgery and downregulated by postoperative treatment with JWH133.ConclusionsThese findings indicate that CB2R may modulate the neuroinflammatory and cognitive impairment in a mouse model of orthopedic surgery, and the activation of CB2R may effectively ameliorate the hippocampal-dependent memory loss of mice in the early postoperative stage.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0913-7) contains supplementary material, which is available to authorized users.

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Heat Shock Protein 72 Overexpression Prevents Early Postoperative Memory Decline after Orthopedic Surgery under General Anesthesia in Mice

Cited by 46 publications

References 47 publications

The fatty acid amide hydrolase inhibitor PF-3845 promotes neuronal survival, attenuates inflammation and improves functional recovery in mice with traumatic brain injury

The fatty acid amide hydrolase inhibitor PF-3845 promotes neuronal survival, attenuates inflammation and improves functional recovery in mice with traumatic brain injury

Surgery Results in Exaggerated and Persistent Cognitive Decline in a Rat Model of the Metabolic Syndrome

Activation of cannabinoid receptor type 2 attenuates surgery-induced cognitive impairment in mice through anti-inflammatory activity

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