Neuroprotective Effects Against POCD by Photobiomodulation: Evidence from Assembly/Disassembly of the Cytoskeleton

Abstract

Postoperative cognitive dysfunction (POCD) is a decline in memory following anaesthesia and surgery in elderly patients. While often reversible, it consumes medical resources, compromises patient well-being, and possibly accelerates progression into Alzheimer's disease. Anesthetics have been implicated in POCD, as has neuroinflammation, as indicated by cytokine inflammatory markers. Photobiomodulation (PBM) is an effective treatment for a number of conditions, including inflammation. PBM also has a direct effect on microtubule disassembly in neurons with the formation of small, reversible varicosities, which cause neural blockade and alleviation of pain symptoms. This mimics endogenously formed varicosities that are neuroprotective against damage, toxins, and the formation of larger, destructive varicosities and focal swellings. It is proposed that PBM may be effective as a preconditioning treatment against POCD; similar to the PBM treatment, protective and abscopal effects that have been demonstrated in experimental models of macular degeneration, neurological, and cardiac conditions.

Keywords: PBM; POCD; cytoskeleton; neuroprotection; photobiomodulation; postoperative cognitive dysfunction.

Figure 1

Formation of neuroprotective endogenous varicosities: (A) confocal laser microscopy images of formation of dendritic varicosities in rat hippocampus neurons treated with 30 μM NMDA; (B) immunofluorescent images of formation of dendritic varicosities (arrows) in rat embryo hippocampus neurons, immediately after exposure to 30 μM NMDA (5 minutes) and reversal of varicosities after recovery (60 minutes); (C) immunohistochemistry image stained for tubulin, showing varicosity formation in embryonic DRG neurons in response to resiniferatoxin activation of TRPV1; (D) two-photon laser scanning images, showing the transient increase in mouse neuron volume before (control), during spreading depression (SD) and after recovery from SD, including a merged image (overlap) showing the overlap (yellow), before volume (green), and during CSD (red).

Figure 2

Formation of preconditioning neuroprotective varicosities: (A) immunofluorescent images of neuronal cultures, showing control (a) and the formation of varicosities (b) following ischemic preconditioning using nonharmful oxygen and glucose deprivation for 30 minutes; (B) confocal laser microscopy images of stem cell-derived neurons stained with calcein green, showing the formation of varicosities (arrows) within 22 minutes of the application of black widow venom still apparent after 24 hours, but reducing after 48 hours.

Figure 3

Confocal laser microscopy of axonal varicosities (arrows) produced by LLLT in cultured rat DRG neurons at wavelengths of 1064 nm (A) (Chan, unpublished) and 830 nm (B–F); (B) varicosity formation after 120 seconds of LLLT; (C) control; (D) reversal of varicosities 24 hours after irradiation; (E) magnified image of an axon showing a single varicosity formed after 30-second irradiation with mitochondria stained red; (F) control.

Figure 4

Varicosities and MT changes due to anesthetics: (A) light photomicrographs of the effect of 2 × 10^–3 M procaine on varicosity formation in cultured neurites from time zero to (a) two hours (b), three hours (c), and four hours (d); (B) scanning electron micrograph of swellings (S) in the neurite in response to 1 × 10⁻³ M procaine; (C) electron micrograph showing the formation of blebs on 3T3 cell surface, due to the disruption of membrane-associated MT and microfilaments after treatment with 0.6 mM tetracaine.

Figure 5

Pathological varicosities: (A) immunofluorescent images of axonal swellings produced during dynamic stretch injury of cultured neurons, stained for tubulin (a), tau (b), amyloid precursor protein (c), and neurofilament (d); (B) immunohistochemical stain against amyloid precursor protein, showing axonal varicosities in the corpus callosum of traumatic brain injury cases, caused by motor vehicle collision (a, e, f), falls (b, c), and blunt force trauma (d); (C) confocal laser microscopy images of putamen tissue from Parkinson’s disease cases, showing varicosities, stained for tyrosine hydroxylase (TH), α-synuclein (s-129), with a merged image; (D) electron micrograph of TH immune reactivity showing an axonal (synaptic) varicosity in rat DRG as a result of sensory and sympathetic interactions; (E) immunostained image of varicosity formation in a neuronal cell culture after exposure to prion protein peptide 106–126, showing varicosities (arrows 1–5); (F) immunohistochemical stains showing varicosities and spheroids in a mouse model of Alzheimer’s disease, stained for neurofilament (a, b, c) and the spinal cord of an early onset Alzheimer’s disease case, stained for amyloid precursor protein (d).