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Published on: January 20, 2023
Propofol limits microglial activation after experimental brain trauma through inhibition of nicotinamide adenine
Tao Luo1, Junfang Wu, Shruti V Kabadi
1* Postdoctoral Research Fellow, † Assistant Professor, ‡ Research Associate, § Postdoctoral Research Fellow, ‖ Research Assistant, # David S. Brown Professor and Director of the Center for Shock Trauma and Anesthesiology Research (STAR), Department of Anesthesiology and Center for STAR, University of Maryland School of Medicine, Baltimore, Maryland.
Background:
Microglial activation is implicated in delayed tissue damage after traumatic brain injury (TBI). Activation of microglia causes up-regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, with the release of reactive oxygen species and cytotoxicity. Propofol appears to have antiinflammatory actions. The authors evaluated the neuroprotective effects of propofol after TBI and examined in vivo and in vitro whether such actions reflected modulation of NADPH oxidase.
Methods:
Adult male rats were subjected to moderate lateral fluid percussion TBI. Effect of propofol on brain microglial activation and functional recovery was assessed up to 28 days postinjury. By using primary microglial and BV2 cell cultures, the authors examined propofol modulation of lipopolysaccharide and interferon-γ-induced microglial reactivity and neurotoxicity.
Results:
Propofol improved cognitive recovery after TBI in novel object recognition test (48 ± 6% for propofol [n = 15] vs. 30 ± 4% for isoflurane [n = 14]; P = 0.005). The functional improvement with propofol was associated with limited microglial activation and decreased cortical lesion volume and neuronal loss. Propofol also attenuated lipopolysaccharide- and interferon-γ-induced microglial activation in vitro, with reduced expression of inducible nitric oxide synthase, nitric oxide, tumor necrosis factor-α, interlukin-1β, reactive oxygen species, and NADPH oxidase. Microglial-induced neurotoxicity in vitro was also markedly reduced by propofol. The protective effect of propofol was attenuated when the NADPH oxidase subunit p22 was knocked down by small interfering RNA. Moreover, propofol reduced the expression of p22 and gp91, two key components of NADPH oxidase, after TBI.
Conclusion:
The neuroprotective effects of propofol after TBI appear to be mediated, in part, through the inhibition of NADPH oxidase.
Insights
Propofol treatment improved cognitive function and reduced brain damage after traumatic brain injury (TBI) by inhibiting nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a key enzyme in inflammation.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Microglial activation contributes to delayed brain damage post-traumatic brain injury (TBI).
- Activated microglia upregulate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, releasing cytotoxic reactive oxygen species.
- Propofol exhibits anti-inflammatory properties.
Purpose of the Study:
- To evaluate the neuroprotective effects of propofol in a rat model of TBI.
- To investigate whether propofol's actions involve the modulation of NADPH oxidase activity in vivo and in vitro.
Main Methods:
- Adult male rats underwent moderate lateral fluid percussion TBI, with propofol's effects on microglial activation and recovery assessed up to 28 days.
- Primary microglial and BV2 cell cultures were used to examine propofol's modulation of inflammatory responses and neurotoxicity induced by lipopolysaccharide and interferon-γ.
- The role of NADPH oxidase was investigated using small interfering RNA to knock down the p22 subunit.
Main Results:
- Propofol significantly improved cognitive recovery in the novel object recognition test compared to isoflurane.
- Propofol administration was associated with reduced microglial activation, smaller cortical lesion volumes, and decreased neuronal loss.
- In vitro, propofol attenuated microglial activation and neurotoxicity, reducing key inflammatory mediators and reactive oxygen species. Knockdown of NADPH oxidase subunit p22 diminished propofol's protective effect, and propofol reduced p22 and gp91 expression post-TBI.
Conclusions:
- Propofol demonstrates significant neuroprotective effects following TBI.
- These protective effects are, at least partly, mediated by the inhibition of NADPH oxidase activity.
