Abstract
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’s 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 mg/kg/day; i.p.) with or without administration of DAHP (0.5 g/kg/day; i.p.) or wortmannin (WM), a PI3K inhibitor, (15 μg/kg/day; i.v.) for 14 days. 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-1α levels. Indeed, DAHP attenuates oxidative stress by increasing SOD activity and Nrf2 expression in addition to reducing neuro-inflammatory status by inhibiting NF-κB p65 and TNF-α 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 via inhibition of GTPCH I and iNOS activity and activation of MasR/PI3K/Akt/CREB/BDNF/TrKB axis besides its antioxidant and anti-inflammatory effect.
Highlights
Huntington’s disease (HD) is a progressive neurodegenerative disease characterized by motor and cognitive dysfunctions together with psychiatric manifestations (Shah et al, 1993; Roos, 2010), for which no cure or disease-modifying therapies are available until now (Tabrizi et al, 2019)
No significant differences were recorded between control group and DAHP group; comparisons were made relative to the control group only
In novel object recognition test, 3-nitropropionic acid (3-NP) treated rats spent significantly less time exploring the novel object than familiar object (31.1%) and less time exploring the novel object in comparison with control group (65.97%) and showed significant decrease in discrimination index and the total time spent exploring both objects (46.12%) that was a clear indication on cognitive deficit
Summary
Huntington’s disease (HD) is a progressive neurodegenerative disease characterized by motor and cognitive dysfunctions together with psychiatric manifestations (Shah et al, 1993; Roos, 2010), for which no cure or disease-modifying therapies are available until now (Tabrizi et al, 2019). Inflammation mediated by microglia plays a crucial role in neurodegenerative diseases as Parkinson’s disease (PD) (Gao et al, 2003), Alzheimer’s disease (AD) (Salvati and Beenhakker, 2019), and HD (Sapp et al, 2001). Sustained and excessive activation of microglia along with massive production of proinflammatory cytokines is responsible, in part, for inflammation-induced neurodegeneration (Block et al, 2007; Glass et al, 2010). Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) in the microglia is one of the chief proinflammatory factors that induce neuronal death (Liu et al, 2012). The overproduction of reactive oxygen species and neuroinflammatory status results in marked elevation of iNOS activity and peroxynitrite (ONOO-) level, causing neuronal death (Pedraza-Chaverrí et al, 2009)
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