Microglial- and Astrocyte-Specific Expression of Purinergic Signaling Components and Inflammatory Mediators in the Rat Hippocampus During Trimethyltin-Induced Neurodegeneration.
Milorad DragićNataša MitrovićMarija AdžićNadežda NedeljkovićIvana GrkovićPublished in: ASN neuro (2022)
The present study examined the involvement of purinergic signaling components in the rat model of hippocampal degeneration induced by trimethyltin (TMT) intoxication (8 mg/kg, single intraperitoneal injection), which results in behavioral and neurological dysfunction similar to neurodegenerative disorders. We investigated spatial and temporal patterns of ecto-nucleoside triphosphate diphosphohydrolase 1 (NTPDase1/CD39) and ecto-5' nucleotidase (eN/CD73) activity, their cell-specific localization, and analyzed gene expression pattern and/or cellular localization of purinoreceptors and proinflammatory mediators associated with reactive glial cells. Our study demonstrated that all Iba1+ cells at the injured area, irrespective of their morphology, upregulated NTPDase1/CD39, while induction of eN/CD73 has been observed at amoeboid Iba1+ cells localized within the hippocampal neuronal layers with pronounced cell death. Marked induction of P2Y 12 R, P2Y 6 R, and P2X 4 -messenger RNA at the early stage of TMT-induced neurodegeneration might reflect the functional properties, migration, and chemotaxis of microglia, while induction of P2X 7 R at amoeboid cells probably modulates their phagocytic role. Reactive astrocytes expressed adenosine A 1 , A 2A , and P2Y 1 receptors, revealed induction of complement component C3, inducible nitric oxide synthase, nuclear factor-kB, and proinflammatory cytokines at the late stage of TMT-induced neurodegeneration. An increased set of purinergic system components on activated microglia (NTPDase1/CD39, eN/CD73, and P2X 7 ) and astrocytes (A 1 R, A 2A R, and P2Y 1 ), and loss of homeostatic glial and neuronal purinergic pathways (P2Y 12 and A 1 R) may shift purinergic signaling balance toward excitotoxicity and inflammation, thus favoring progression of pathological events. These findings may contribute to a better understanding of the involvement of purinergic signaling components in the progression of neurodegenerative disorders that could be target molecules for the development of novel therapies.
Keyphrases
- induced apoptosis
- cell cycle arrest
- cell death
- gene expression
- oxidative stress
- early stage
- nuclear factor
- neuropathic pain
- inflammatory response
- diabetic rats
- cerebral ischemia
- nk cells
- nitric oxide
- endoplasmic reticulum stress
- signaling pathway
- poor prognosis
- squamous cell carcinoma
- cell therapy
- brain injury
- lipopolysaccharide induced
- subarachnoid hemorrhage
- lymph node
- single molecule
- high speed
- atomic force microscopy