{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T03:17:56Z","timestamp":1790047076759,"version":"4.0.1"},"reference-count":71,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T00:00:00Z","timestamp":1640131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>GTP cyclohydrolase I (GTPCH I) is the rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis; the latter is an essential factor for iNOS activation that contributes neuronal loss in Huntington\u2019s disease (HD). The aim of the study was to investigate the neuroprotective effect of 2,4-diamino-6-hydroxypyrimidine (DAHP), GTPCH I enzyme inhibitor, against neuronal loss in 3-nitropropinic acid (3-NP)-induced HD in rats and to reveal the possible involved mechanisms mediated through PI3K\/Akt axis and its correlation to Mas receptor (MasR). Rats received 3-NP (10\u00a0mg\/kg\/day; i.p.) with or without administration of DAHP (0.5\u00a0g\/kg\/day; i.p.) or wortmannin (WM), a PI3K inhibitor, (15\u00a0\u03bcg\/kg\/day; i.v.) for 14\u00a0days. DAHP improved cognitive, memory, and motor abnormalities induced by 3-NP, as confirmed by striatal histopathological specimens and immunohistochemical examination of GFAP. Moreover, DAHP treatment inhibited GTPCH I activity, resulting in decreased BH4 levels and iNOS activation. Also, DAHP upregulated the protein expression of survival protein; p85\/p55 (pY458\/199)-PI3K and pS473-Akt that, in turn, boosted the activation of striatal neurotrophic factors and receptor, pS133-CREB, BDNF and pY515-TrKB, which positively affect MasR protein expression and improve mitochondrial dysfunction, as indicated by enhancing both SDH and PGC-1\u03b1 levels. Indeed, DAHP attenuates oxidative stress by increasing SOD activity and Nrf2 expression in addition to reducing neuro-inflammatory status by inhibiting NF-\u03baB p65 and TNF-\u03b1 expression. Interestingly, all the previous effects were blocked by co-administration of WM with DAHP. In conclusion, DAHP exerts neuroprotective effect against neuronal loss induced by 3-NP administration <jats:italic>via<\/jats:italic> inhibition of GTPCH I and iNOS activity and activation of MasR\/PI3K\/Akt\/CREB\/BDNF\/TrKB axis besides its antioxidant and anti-inflammatory effect.<\/jats:p>","DOI":"10.3389\/fphar.2021.740966","type":"journal-article","created":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T06:29:13Z","timestamp":1640154553000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":32,"title":["Inhibition of Brain GTP Cyclohydrolase I Attenuates 3-Nitropropionic Acid-Induced Striatal Toxicity: Involvement of Mas Receptor\/PI3k\/Akt\/CREB\/ BDNF Axis"],"prefix":"10.3389","volume":"12","author":[{"given":"Aya M.","family":"Mustafa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mostafa A.","family":"Rabie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hala F.","family":"Zaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya M.","family":"Shaheen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3927","DOI":"10.1007\/s12035-015-9303-2","article-title":"Role of Rho Kinase Inhibition in the Protective Effect of Fasudil and Simvastatin against 3-nitropropionic Acid-Induced Striatal Neurodegeneration and Mitochondrial Dysfunction in Rats","volume":"53","author":"Ahmed","year":"2016","journal-title":"Mol. 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