GPR39 Deficiency Impairs Memory and Alters Oxylipins and Inflammatory Cytokines Without Affecting Cerebral Blood Flow in a High-Fat Diet Mouse Model of Cognitive Impairment

Abstract

Vascular cognitive impairment (VCI) is the second most common cause of dementia. There is no treatment for VCI, in part due to a lack of understanding of the underlying mechanisms. The G-protein coupled receptor 39 (GPR39) is regulated by arachidonic acid (AA)-derived oxylipins that have been implicated in VCI. Furthermore, GPR39 is increased in microglia of post mortem human brains with VCI. Carriers of homozygous GPR39 SNPs have a higher burden of white matter hyperintensity, an MRI marker of VCI. We tested the hypothesis that GPR39 plays a protective role against high-fat diet (HFD)-induced cognitive impairment, in part mediated via oxylipins actions on cerebral blood flow (CBF) and neuroinflammation. Homozygous (KO) and heterozygous (Het) GPR39 knockout mice and wild-type (WT) littermates with and without HFD for 8 months were tested for cognitive performance using the novel object recognition (NOR) and the Morris water maze (MWM) tests, followed by CBF measurements using MRI. Brain tissue and plasma oxylipins were quantified with high-performance liquid chromatography coupled to mass spectrometry. Cytokines and chemokines were measured using a multiplex assay. KO mice, regardless of diet, swam further away from platform location in the MWM compared to WT and Het mice. In the NOR test, there were no effects of genotype or diet. Brain and plasma AA-derived oxylipins formed by 11- and 15-lipoxygenase (LOX), cyclooxygenase (COX) and non-enzymatically were increased by HFD and GPR39 deletion. Interleukin-10 (IL-10) was lower in KO mice on HFD than standard diet (STD), whereas IL-4, interferon γ-induced protein-10 (IP-10) and monocyte chemotactic protein-3 (MCP-3) were altered by diet in both WT and KO, but were not affected by genotype. Resting CBF was reduced in WT and KO mice on HFD, with no change in vasoreactivity. The deletion of GPR39 did not change CBF compared to WT mice on either STD or HFD. We conclude that GPR39 plays a role in spatial memory retention and protects against HFD-induced cognitive impairment in part by modulating inflammation and AA-derived oxylipins. The results indicate that GPR39 and oxylipin pathways play a role and may serve as therapeutic targets in VCI.

Signaling pathway mechanisms of neurological diseases induced by G protein‐coupled receptor 39

“… 78 , 79 In addition, a high‐fat diet and a standard diet exhibit impaired spatial memory in the absence of GPR39. 80 Moreover, GPR39 regulates oxygen lipid synthesis, and GPR39 deletion induces the AA COX metabolites PGE2 and PGD2, 15‐keto PGF2a, and DHA 12/15‐LOX metabolite resolvin D1, indicating that constitutive GPR39 activity suppresses COX and 12/15‐LOX. These oxygenated lipid synthases and GPR39 may serve as biomarkers or targets for VCI therapy.…”

“…These oxygenated lipid synthases and GPR39 may serve as biomarkers or targets for VCI therapy. 80 At present, many studies have reported on the relationship between zinc and dementia, but there are still controversies. Although most studies suggest that zinc is beneficial, some scholars still believe that zinc has neurotoxicity, which may be explained by the different binding sites between different concentrations of zinc and APP.…”

“…GPR39 can also regulate the expression of key elements in age‐related inhibitory neurotransmission 78,79 . In addition, a high‐fat diet and a standard diet exhibit impaired spatial memory in the absence of GPR39 80 . Moreover, GPR39 regulates oxygen lipid synthesis, and GPR39 deletion induces the AA COX metabolites PGE2 and PGD2, 15‐keto PGF2a, and DHA 12/15‐LOX metabolite resolvin D1, indicating that constitutive GPR39 activity suppresses COX and 12/15‐LOX.…”

Profiling of Oxylipins as Markers of Oxidative Stress in Biological Samples

“…Oxylipin profiling has utility for assessing oxidative stress, inflammatory status, and disease risk (Bah et al., 2022; Karu et al., 2022; Le et al., 2021). Generally, oxylipins derived from arachidonic acids, commonly referred as eicosanoids, are considered pro‐inflammatory lipid mediators.…”

“…Because our previously described methodology requires chemical synthesis of (labeled) mercapturic acid metabolites that are not commercially available, these oxylipin metabolites never gained great popularity as biomarkers of oxidative stress. In recent years, our laboratory adapted and validated measurement of semi‐stable oxylipins, many of which are now commercially available and for which data have become increasingly available in the literature for comparison purposes (Bah et al., 2022; Le et al., 2021). However, accurate and precise quantification of oxylipins derived from arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) remains challenging due to their very low levels in the body, their chemical stability, and issues with recovery from biological samples.…”