Table 3.
Effects of HT and derivatives in animal models.
| Study | Animal Model | Compounds Tested | Dose | Route of Administration | Significant Outcomes | Ref. |
|---|---|---|---|---|---|---|
| Arunsundar et al., 2015 | C57BL/6 mice treated with Aβ1–42 plus oA42i | HT | 10 mg/kg/day for two weeks | Oral gavage | Reduction in brain pro-inflammatory factors (IL-18, IL-6, and COX-2) and modulation of MAPK signaling. Restoration of Bcl-2/Bad levels and activation of caspase-dependent mitochondria-mediated apoptotic pathway involving cytochrome c, APAF-1, and caspase-9/3. | [48] |
| Zheng et al., 2015 | Specific pathogen-free female Sprague–Dawley rats exposed to restraint stress | HT | 10–50 mg/kg/day for two weeks before mating | Oral | Prevention of stress-induced downregulation of neural proteins BDNF, GAP43, synaptophysin, NMDAR1, NMDANR2A, and NMDANR2B. Increase of transcription factors FOXO1 and FOXO3, and phase II enzyme-related proteins Nrf2 and HO-1. | [53] |
| Peng et al., 2016 | Transgenic APP/PS1 mice | HT | 5 mg/kg/day for six months | Oral gavage | Modulation of mitochondrial oxidative dysfunction, measured as reduction in mitochondrial carbonyl proteins and GSSG, increased SOD expression, and restoration of phase II enzymes. Restoration of p38 and JNK/MAPK signaling and attenuation of inflammation in the cerebral cortex. Inhibition of brain apoptotic responses. | [47] |
| Nardiello et al., 2018 | TgCRND8 and wild type mice | HT | 50 mg/kg for four weeks | Oral gavage | Reduction in Aβ42 and pE3-Aβ deposits in the cortex and hippocampus. Reduction in TNF-α expression, astrocyte reaction, and modulation of MAPKs signaling. | [61] |
| Calahorra et al., 2019 | Male C57BL/6JRj mice which underwent transient occlusion of the right middle cerebral artery | HT | 45 mg/kg/day for five weeks | Oral (Incorporated into the pellets) | Improved recovery after ischemic stroke by ameliorating stroke-associated learning and motor impairments. Increase in cerebral blood flow, functional and structural connectivity, and anti-inflammatory and neurogenic activity. | [60] |
| Brunetti et al., 2020 | Wild type C. elegans strain N2 (Var. Bristol) and transgenic C. elegans strain OW13 | HT | 30 μg/mL, 100 μg/mL, 250 μg/mL and 500 μg/mL, | Oral | Enhancement of locomotion in worms suffering from α-synuclein-expression in muscles or rotenone exposure, reduction in α-synuclein accumulation in muscles cells, and prevention of neurodegeneration in α-synuclein-containing dopaminergic neurons. | [62] |
| D’Andrea et al., 2020 | Btg1 knockout and Bgt1 wildtype strains (C57BL/6 background) mice | HT | 100 mg/kg/day for 13 days | Oral (in drinking water) | Activation of neurogenesis in the dentate gyrus, increase of new neurons survival, and decrease of neuronal apoptosis. | [59] |
| Di Rosa et al., 2020 | Wild type C. elegans strain N2 (Var. Bristol) and transgenic C. elegans strain OW13 | HT | 100–500 μg/mL. | Oral | Reduction in neurodegeneration, increase of locomotion in worms suffering from α-synuclein-expression in muscles or rotenone exposure and prevention of α-synuclein accumulation. | [63] |
| Pérez-Barrón et al., 2020 | Male Wistar rats PD model treated with MPP+ | HT | Single dose 1.5 mg/kg | Intravenous | Reduction in ipsilateral rotations, correlated with the preservation of striatal dopamine levels, due to the inhibitory effect on MAO activity. | [56] |
| Zhang et al., 2020 | Male C57BL/6 mice treated with LPS | HT | Single dose 100 mg/kg | Oral gavage | Reduction in some pro-inflammatory mediators (COX-2, iNOS, TNF-α, IL-1β) levels and microglia/astrocyte activation in the brain. | [51] |
| Pathania et al., 2021 | Male C57BL/6 mice treated with MPTP | HT | 50 mg/kg/day for 1 week before and after MPTP | Oral gavage | Restoration of brain dopamine levels and prevention dopaminergic neurons loss in the substantia nigra and striatum by MAO-B inhibition. | [58] |
| Pérez-Barrón et al., 2021 | Male Wistar rats PD model treated with MPP+ | HT, HT acetate and nitro-HT | Single dose 1.5 mg/kg | Intravenous | Protection from dopamine neuron degeneration, restoration of MPP+-induced redox unbalance, decrease of lipid peroxidation products and rise of GSH/GSSG ratio. | [57] |
| Qin et al., 2021 | Transgenic APP/PS1 mice | HT acetate | 50 mg/kg/day for twelve weeks | Oral gavage | Improved escape latency and distance, and the number of platform crossings of AD mice in the water maze test by ameliorating neuronal apoptosis and modulating NF-ĸB activity and MAPK signaling. | [52] |
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenylpyridinium (MPP+), amyloid precursor protein/presenilin-1 (APP/PS1), amyloid β42 (Aβ42), apoptotic protease activating factor-1 (APAF-1), brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), chronic unpredictable mild stress (CUMS), cyclooxygenase-2 (COX-2), forkhead box protein O1 and O3 (FOXO1, FOXO3), glial fibrillary acidic protein (GFAP), glutathione reduced (GSH), glutathione oxidized (GSSG), Growth Associated Protein 43 (GAP43), heme-oxygenase-1 (HO-1), hypothalamic-Pituitary-Adrenal (HPA), ibotenic acid (oA42i), inducible nitric oxide synthase (iNOS), interleuchin 1β, 6, 18 (IL-1β, IL-6, IL-18), Janus kinase/mitogen-activated protein kinase (JNK/MAPK), monoaminoxidase (MAO), N-methyl-D-aspartate receptor 1/2A/2B (NMDAR1, NMDANR2A, NMDANR2B), nuclear factor erythroid 2–related factor 2 (Nrf2), nuclear factor ĸB (NF-κB), pyroglutamate-modified Abeta (pE3-Aβ), superoxide dismutase (SOD), tropomyosin receptor kinase B (TrkB), tumor necrosis factor α (TNF-α).