Peripheral inflammation induces long-term changes in tyrosine hydroxylase activation in the substantia nigra

Ong, Lin Kooi ORCID: and Briggs, Gabrielle D. and Guan, Liying and Dunkley, Peter R. and Dickson, Phillip W. (2021) Peripheral inflammation induces long-term changes in tyrosine hydroxylase activation in the substantia nigra. Neurochemistry International, 146:105022. pp. 1-10. ISSN 0197-0186


Inflammation plays a role in neuropathology. We hypothesised that inflammation, induced by a single intraperitoneal injection of lipopolysaccharide (LPS), would induce long-term changes in the regulation of tyrosine hydroxylase (TH) in the rat midbrain. The level of 12 cytokines was initially analysed from one day to six months after LPS injection to confirm that peripheral inflammation led to neuroinflammatory changes in the midbrain. In the substantia nigra (SN), the levels of 8 of the 12 measured cytokines was significantly increased at one day. Granulocyte-macrophage colony-stimulating factor showed a threefold increased level at 6 months. The ventral tegmental area (VTA) showed a completely different pattern, with no increases in the levels of the 12 cytokines at one day and no changes beyond one week. TH activity was determined using a tritiated water release assay, TH protein and phosphorylation levels (Ser19, Ser31 and Ser40) were determined using western blotting. TH-specific activity in the SN was unchanged at one day but was substantially increased at one week and one month with no concomitant increase in TH phosphorylation. Substantial changes in TH activation without changes in TH phosphorylation have not previously been observed in the brain in response to a range of stressors. TH-specific activity was increased in the SN, and in the caudate putamen, at 6 months and was associated with increased TH phosphorylation at Ser19 and Ser40 at both locations. TH-specific activity in the VTA showed only a transient increase at day one associated with increased phosphorylation at Ser19 and Ser31 but thereafter showed no changes. This study shows that inflammation induced by LPS generated two distinct long-term changes in TH activity in the SN that are caused by different mechanisms, but there were no long-term changes in the adjacent VTA.

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Item Type: Article (Commonwealth Reporting Category C)
Refereed: Yes
Item Status: Live Archive
Additional Information: Files associated with this item cannot be displayed due to copyright restrictions.
Faculty/School / Institute/Centre: No Faculty
Faculty/School / Institute/Centre: No Faculty
Date Deposited: 10 Jun 2022 01:17
Last Modified: 13 Jun 2022 01:37
Uncontrolled Keywords: Activity; Inflammation; Lipopolysaccharide; Phosphorylation; Substantia nigra; Tyrosine hydroxylase
Fields of Research (2020): 32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320499 Immunology not elsewhere classified
32 BIOMEDICAL AND CLINICAL SCIENCES > 3205 Medical biochemistry and metabolomics > 320506 Medical biochemistry - proteins and peptides (incl. medical proteomics)
32 BIOMEDICAL AND CLINICAL SCIENCES > 3209 Neurosciences > 320902 Cellular nervous system
Socio-Economic Objectives (2020): 20 HEALTH > 2001 Clinical health > 200101 Diagnosis of human diseases and conditions
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