Itaconate alleviates β2-microglobulin-induced cognitive impairment by enhancing the hippocampal amino-β-carboxymuconate-semialdehyde-decarboxylase/picolinic acid pathway

  • Biochem Pharmacol. 2022 Aug:202:115137. doi: 10.1016/j.bcp.2022.115137.
Gui-Juan Zhou  1 ,  Yi-Yun Tang  2 ,  Jin-Xi Zuo  3 ,  Tao Yi  3 ,  Jun-Peng Tang  3 ,  Ping Zhang  4 ,  Wei Zou  5 ,  Xiao-Qing Tang  6
Affiliations
  • 1. The First Affiliated Hospital, Institute of Neurology, Hengyang Medical School, University of South China, Hengyang 42100, Hunan, PR China; Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Institute of Neuroscience, Hengyang Medical School, University of South China, Hengyang 42100, Hunan, PR China.
  • 2. Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Institute of Neuroscience, Hengyang Medical School, University of South China, Hengyang 42100, Hunan, PR China.
  • 3. Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Institute of Neuroscience, Hengyang Medical School, University of South China, Hengyang 42100, Hunan, PR China; The Affiliated Nanhua Hospital, Department of Neurology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, PR China.
  • 4. The Affiliated Nanhua Hospital, Department of Neurology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, PR China.
  • 5. The Affiliated Nanhua Hospital, Department of Neurology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, PR China. Electronic address: [email protected].
  • 6. The First Affiliated Hospital, Institute of Neurology, Hengyang Medical School, University of South China, Hengyang 42100, Hunan, PR China; Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Institute of Neuroscience, Hengyang Medical School, University of South China, Hengyang 42100, Hunan, PR China. Electronic address: [email protected].
PMID: 35700758 DOI: 10.1016/j.bcp.2022.115137
Abstract

β2-microglobulin (B2M) has been established to impair cognitive function. However, no treatment is currently available for B2M-induced cognitive dysfunction. Itaconate is a tricarboxylic acid (TCA) cycle intermediate that exerts neuroprotective effects in several neurological diseases. The amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD)/picolinic acid (PIC) pathway is a crucial neuroprotective branch in the kynurenine pathway (KP). The present study sought to investigate whether Itaconate attenuates B2M-induced cognitive impairment and examine the mediatory role of the hippocampal ACMSD/PIC pathway. We demonstrated that 4-Octyl Itaconate (OI, an itaconate derivative) significantly alleviated B2M-induced cognitive dysfunction and hippocampal neurogenesis impairment. OI treatment also increased the expression of ACMSD, elevated the concentration of PIC, and decreased the level of 3-HAA in the hippocampus of B2M-exposed rats. Furthermore, inhibition of ACMSD by TES-991 significantly abolished the protections of Itaconate against B2M-induced cognitive impairment and neurogenesis deficits. Exogenous PIC supplementation in hippocampus also improved cognitive performance and hippocampal neurogenesis in B2M-exposed rats. These findings demonstrated that Itaconate alleviates B2M-induced cognitive impairment by upregulation of the hippocampal ACMSD/PIC pathway. This is the first study to document Itaconate as a promising therapeutic agent to ameliorate cognitive impairment. Moreover, the mechanistic insights into the ACMSD/PIC pathway improve our understanding of it as a potential therapeutic target for neurological diseases beyond B2M-associated neurocognitive disorders.

Keywords
Amino-β-carboxymuconate-semialdehyde-decarboxylase; Cognitive impairment; Itaconate; Neurogenesis; Picolinic acid; β(2)-microglobulin.
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