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Prefrontal cortex infusion of beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, produces antidepressant-like effects in a rodent model of depression.

ABSTRACT: Aims: Neuroinflammation is deeply related to the pathophysiology of depression. Beta-hydroxybutyrate (BHB), which is an endogenous ketone body, exerts anti-inflammatory effects, and peripheral administration of BHB induces antidepressant effects in an animal model of depression; however, it is unclear whether BHB specifically mediates these actions in the brain. Thus, we administered BHB directly into the brain in a rodent model of depression using a chronic unpredictable stress (CUS) paradigm.

Methods: BHB was continuously microinjected into the prefrontal cortex (PFC) using osmotic pumps for 21 days. Behavioral testing included the forced swim test (FST) and the open field test (OFT); the levels of pro-inflammatory cytokines, such as interleukin 1? (IL-1?) and tumor necrosis factor ? (TNF-?), were quantified in the PFC, and the concentration of corticosterone in blood serum was measured.

Results: BHB administration into the PFC significantly decreased immobility time in the FST, without significantly altering locomotor activity assessed in the OFT. Also, CUS significantly increased the levels of TNF-? in the PFC and decreased serum corticosterone levels; these changes were attenuated by BHB administration. These findings suggest that a small amount of BHB administered into the PFC directly produces antidepressant effects, possibly through anti-inflammatory mechanisms, and can improve hypothalamus-pituitary-adrenal axis responses.

Conclusion: BHB may be a novel therapeutic candidate for the treatment of depression based on the neuro-inflammatory hypothesis, and the PFC is a region implicated in the antidepressant action of BHB.

SUBMITTER: Kajitani N

PROVIDER: S-EPMC7722664 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Prefrontal cortex infusion of beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, produces antidepressant-like effects in a rodent model of depression.

Kajitani Naofumi N Iwata Masaaki M Miura Akihiko A Tsunetomi Kyohei K Yamanashi Takehiko T Matsuo Ryoichi R Nishiguchi Tsuyoshi T Fukuda Saki S Nagata Mayu M Shibushita Midori M Yamauchi Takahira T Pu Shenghong S Shirayama Yukihiko Y Watanabe Ken K Kaneko Koichi K

Neuropsychopharmacology reports 20200303 2

<h4>Aims</h4>Neuroinflammation is deeply related to the pathophysiology of depression. Beta-hydroxybutyrate (BHB), which is an endogenous ketone body, exerts anti-inflammatory effects, and peripheral administration of BHB induces antidepressant effects in an animal model of depression; however, it is unclear whether BHB specifically mediates these actions in the brain. Thus, we administered BHB directly into the brain in a rodent model of depression using a chronic unpredictable stress (CUS) par ...[more]

PMID: 32125791

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Project description:The ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP. BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet. Prolonged fasting reduces inflammation; however, the impact that ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown. We report that BHB, but neither AcAc nor the structurally related short-chain fatty acids butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to urate crystals, ATP and lipotoxic fatty acids. BHB did not inhibit caspase-1 activation in response to pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome and did not affect non-canonical caspase-11, inflammasome activation. Mechanistically, BHB inhibits the NLRP3 inflammasome by preventing K(+) efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on chirality or starvation-regulated mechanisms like AMP-activated protein kinase (AMPK), reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocks the NLRP3 inflammasome without undergoing oxidation in the TCA cycle, and independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), the G protein-coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome-mediated interleukin (IL)-1β and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such as Muckle-Wells syndrome, familial cold autoinflammatory syndrome and urate crystal-induced peritonitis. Our findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome.

Project description:Background and purposePhosphodiesterase 4 (PDE4) inhibitors produce potent antidepressant-like and cognition-enhancing effects. However, their clinical utility is limited by the major side effect of emesis, which appears to be PDE4 isoform-specific. Although PDE4D subtype plays the pivotal role in these therapeutic profiles, it is also the primary subtype responsible for emesis. Therefore, the aim of present research was to investigate whether long-form PDE4D variants mediate antidepressant-like and cognition-enhancing effects, but are irrespective with emesis.Experimental approachIn mice microinfused with lentiviral vectors that contained shRNA-mir hairpin structure targeting long-form PDE4Ds into bilateral prefrontal cortices, the tail-suspension and forced-swim tests were used to measure antidepressant-like effects; novel object recognition and Morris water-maze tasks were used to determine cognition-enhancing effects. The emetic potential was assessed by alpha2 adrenergic receptor-mediated anaesthesia, a surrogate measure of emesis. Intracellular cAMP signalling was analysed by time-resolved FRET immunoassay and Western-blot. Dendritic complexity was assessed by Golgi staining.Key resultsMicroinfusions of lentiviral PDE4D-shRNA down-regulated PDE4D4 and PDE4D5, and imitated the antidepressant-like and cognition-enhancing effects of the prototypical PDE4 inhibitor rolipram. The behavioural effects were related to dendritic complexity and mediated by the increased cAMP signalling. In addition, these effects were not enhanced in the presence of rolipram. Finally, while rolipram shortened the duration of combined anaesthesia, RNA interference-mediated PDE4D knock-down in the prefrontal cortex did not.Conclusion and implicationsThese data suggest that long-form PDE4Ds, at least PDE4D4 and PDE4D5, may be the promising targets for the development of PDE4 variant-selective inhibitors as the new pharmacotherapies for depressive disorders and neurodegenerative diseases involving memory deficits.

Dataset Information

Prefrontal cortex infusion of beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, produces antidepressant-like effects in a rodent model of depression.

Publications

Prefrontal cortex infusion of beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, produces antidepressant-like effects in a rodent model of depression.

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