The brain is both the orchestrator as well as the target of the innate immune system's response to the aseptic trauma of surgery. When trauma-induced inflammation is not appropriately regulated persistent neuro-inflammation interferes with the synaptic plasticity that underlies the learning and memory aspects of cognition. The complications that ensue, include postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) at two poles of a constellation that is now termed perioperative neurocognitive disorders. While the relationship of acute POD to the more indolent POCD is not completely understood both can be further complicated by earlier-onset of dementia and higher mortality. How and why these disorders occur is the focus of this report. The innate immune system response to peripheral trauma signals to the brain through a regulated cascade of cellular and molecular actors producing a teleological defense mechanism, "sickness behavior," to curtail further injury and initiate repair. Sickness behavior, including disordered cognition, is terminated by neural and humoral pathways that restore homeostasis and launch the organism on a path to good health. With so many "moving parts" the innate immune system is vulnerable in clinical settings that include advanced age and lifestyle-induced diseases such as "unhealthy" obesity and the inevitable insulin resistance. Under these conditions, inflammation may become exaggerated and long-lived. Consideration is provided how to identify the high-risk surgical patient and both pharmacological (including biological compounds) and non-pharmacological strategies to customize care.
Background: Postoperative cognitive decline (PCD) requires microglial activation. Voltage-gated Kv1.3 potassium channels are involved in microglial activation. We determined the role of Kv1.3 in PCD and the efficacy and safety of inhibiting Kv1.3 with phenoxyalkoxypsoralen-1 (PAP-1) in preventing PCD in a mouse model. Methods: After institutional approval, we assessed whether Kv1.3-deficient mice (Kv1.3 e/e ) exhibited PCD, evidenced by tibial-fracture surgery-induced decline in aversive freezing behaviour, and whether PAP-1 could prevent PCD and postoperative neuroinflammation in PCD-vulnerable diet-induced obese (DIO) mice. We also evaluated whether PAP-1 altered either postoperative peripheral inflammation or tibial-fracture healing. Results: Freezing behaviour was unaltered in postoperative Kv1.3 e/e mice. In DIO mice, PAP-1 prevented postoperative (i) attenuation of freezing behaviour (54 [17.3]% vs 33.4 [12.7]%; P¼0.03), (ii) hippocampal microglial activation by size (130 [31] pixels vs 249 [49]; P<0.001) and fluorescence intensity (12 000 [2260] vs 20 800 [5080] absorbance units; P<0.001), and (iii) hippocampal upregulation of interleukin-6 (IL-6) (14.9 [5.7] vs 25.6 [10.4] pg mg À1 ; P¼0.011). Phenoxyalkoxypsoralen-1 neither affected surgery-induced upregulation of plasma IL-6 nor cartilage and bone components of the surgical fracture callus.Conclusions: Microglial-mediated PCD requires Kv1.3 activity, determined by genetic and pharmacological targeting approaches. Phenoxyalkoxypsoralen-1 blockade of Kv1.3 prevented surgery-induced hippocampal microglial activation and neuroinflammation in mice known to be vulnerable to PCD. Regarding perioperative safety, these beneficial effects of PAP-1 treatment occurred without impacting fracture healing. Kv1.3 blockers, currently undergoing clinical trials for other conditions, may represent an effective and safe intervention to prevent PCD.
The aseptic trauma of peripheral surgery activates a systemic inflammatory response that results in neuro-inflammation; the microglia, the resident immunocompetent cells in the brain, are a key element of the neuroinflammatory response. In most settings microglia perform a surveillance role in the brain detecting and responding to “invaders” to maintain homeostasis. However, microglia have also been implicated in producing harm possibly by changing its phenotype from its beneficial, anti-inflammatory state (termed M2) into an injurious pro-inflammatory state (termed M1); it is likely that there are intermediates states between these polar phenotypes and some consider that a gradient exists with a number of intermediates, rather than a strict dichotomy between M1 and M2. In the pro-inflammatory phenotypes, microglia can disrupt synaptic plasticity such as long- term potentiation that can result in disorders of learning and memory of the type observed in Peri-operative Neurocognitive Disorders. Therefore, investigators have sought strategies to prevent microglia from provoking this adverse event in the perioperative period. In preclinical studies microglia can be depleted by removing trophic factors required for its maintenance; subsequent repopulation with a more beneficial microglial phenotype may result in memory enhancement, improved sensory motor function, as well as suppression of neuroinflammatory and oxidative stress pathways. Another approach consists of preventing microglial activation using the non-specific P38 MAP kinase blockers such as minocycline. Perhaps a more physiologic approach is the use of inhibitors of potassium (K+) channels that are required to convert the microglia into an active state. In this context the specific K+ channels that are implicated are termed Kv1.3 and KCa3.1 and high selective inhibitors for each have been developed. Data are accumulating demonstrating the utility of these K+ channel blockers in preventing Perioperative Neurocognitive Disorders.
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