Heba R. Ghaiad

Paclitaxel (PTX)-induced peripheral neuropathy (PIPN) is a disabling side effect of PTX, which adversely affects the life quality of cancer patients. Flavonoids such as hesperidin methyl chalcone (HMC) and taxifolin (TAX) can alleviate neuropathic pain via their anti-inflammatory, antioxidant, neuroprotective, and antinociceptive properties. The current study aimed to assess the efficacy of HMC and TAX in preventing PIPN individually or in combination. Pretreatment with HMC and TAX mitigated PTX-induced mechanical allodynia and hyperalgesia, cold allodynia, and thermal hyperalgesia as well as restore the normal histological architecture. Remarkably, neuropathic pain was relieved by suppression of nerve growth factor (NGF), p38 mitogen-activated protein kinase (p38 MAPK), and transient receptor potential vanilloid type-1 (TRPV1), which ultimately lead to reduced calcitonin gene-related peptide (CGRP). Furthermore, both HMC or TAX enhanced nuclear factor erythroid 2-related factor 2 (Nrf2), leading to elevated glutathione (GSH) and total antioxidant capacity (TAC) along with lowered malondialdehyde (MDA), which in turn, downregulated nuclear factor kappa B P65 (NF-κB P65) and its phosphorylated form and eventually reduced tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) then lowered the apoptotic indices. Promisingly, the combination of both agents was superior to each drug alone through targeting more diverse signaling pathways and achieving synergistic and comprehensive therapeutic effects. In conclusion, pretreatment with HMC and TAX separately or in combination alleviated PIPN via modulating NGF/p38 MAPK/NF-κB P65/TRPV1/CGRP pathway.

BACKGROUND: Huntington's disease (HD) is a progressive neurodegenerative disease that causes motor, cognitive, and psychiatric abnormalities, with no satisfying disease-modifying therapy so far. 3-nitropropionic acid (3NP) induces behavioural deficits, together with biochemical and histological alterations in animals' striata that mimic HD. The role of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome in HD pathogenesis remains largely uncharacterized. Parthenolide (PTL), a naturally occurring nuclear factor kappa B (NF-κB) inhibitor, is also known to inhibit NLRP3 inflammasome. Whether PTL is beneficial in HD has not been established yet.

AIM: This study evaluated the possible neuroprotective effects of PTL against 3NP-induced behavioural abnormalities, striatal biochemical derangements, and histological aberrations.

METHODS: Male Wistar rats received PTL (0.5 mg/kg/day, i.p) for 3 weeks and 3NP (10 mg/kg/day, i.p) was administered alongside for the latter 2 weeks to induce HD. Finally, animals were subjected to open-field, Morris water maze and rotarod tests. Rat striata were examined histologically, striatal protein expression levels of glial fibrillary acidic protein (GFAP), cluster of differentiation 45 (CD45) and neuron-specific enolase (NSE) were evaluated immunohistochemically, while those of interleukin (IL)-1β, IL-18, ionized calcium-binding adapter molecule-1 (Iba1) and glutamate were determined by ELISA. Striatal nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein (Keap1), NF-κB, NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, S100 calcium-binding protein A10 (S100A10) and complement-3 (C3) were assessed by gene expression analysis.

RESULTS: PTL improved motor, locomotor, cognitive and anxiety-like behaviours, restored neuronal integrity, upregulated Nrf2, and inhibited NLRP3 inflammasome, NF-κB and microglial activation. Additionally, PTL induced astrocyte shifting towards the neuroprotective A2 phenotype.

CONCLUSION: PTL exhibits neuroprotection against 3NP-induced HD, that might be ascribed, at least in part, to its modulatory effects on Keap1/Nrf2 and NF-κB/NLRP3 inflammasome signaling.

Ivermectin is a US Food and Drug Administration (FDA)-approved antiparasitic agent with antiviral and anti-inflammatory properties. Although recent studies reported the possible anti-inflammatory activity of ivermectin in respiratory injuries, its potential therapeutic effect on pulmonary fibrosis (PF) has not been investigated. This study aimed to explore the ability of ivermectin (0.6 mg/kg) to alleviate bleomycin-induced biochemical derangements and histological changes in an experimental PF rat model. This can provide the means to validate the clinical utility of ivermectin as a treatment option for idiopathic PF. The results showed that ivermectin mitigated the bleomycin-evoked pulmonary injury, as manifested by the reduced infiltration of inflammatory cells, as well as decreased the inflammation and fibrosis scores. Intriguingly, ivermectin decreased collagen fiber deposition and suppressed transforming growth factor-‍β1 (TGF-‍β1) and fibronectin protein expression, highlighting its anti-fibrotic activity. This study revealed for the first time that ivermectin can suppress the nucleotide-binding oligomerization domain (NOD)‍-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, as manifested by the reduced gene expression of and the apoptosis-associated speck-like protein containing a caspase recruitment domain (), with a subsequent decline in the interleukin‍-‍1β (IL‍-‍1β) level. In addition, ivermectin inhibited the expression of intracellular nuclear factor-‍κB (NF‍-‍κB) and hypoxia‑inducible factor‑1α (HIF‍-‍1α) proteins along with lowering the oxidative stress and apoptotic markers. Altogether, this study revealed that ivermectin could ameliorate pulmonary inflammation and fibrosis induced by bleomycin. These beneficial effects were mediated, at least partly, via the downregulation of TGF-‍β1 and fibronectin, as well as the suppression of NLRP3 inflammasome through modulating the expression of HIF‑1α and NF-‍κB.

Radiation has been applied in cancer treatment to eradicate tumors and displayed great therapeutic benefits for humans. However, it is associated with negative impacts on normal cells, not only cancer cells. Irradiation can trigger cell death through several mechanisms, such as apoptosis, necrosis, and autophagy. This study aimed to investigate the radioprotective efficacy of ubiquinol against radiation-induced splenic tissue injury in animals and the related involved mechanisms. Animals were classified into four groups: group 1 (normal untreated rats) received vehicle 5 % Tween 80; group 2 received 7 Gy γ-radiation; group 3 received 10 mg/Kg oral ubiquinol post-irradiation; and group 4 received 10 mg/Kg oral ubiquinol before and after (pre/post-) irradiation. Ubiquinol restored the spleen histoarchitecture, associated with improved immunohistochemical quantification of B and T lymphocyte markers and ameliorated hematological alterations induced by irradiation. Such effects may be due to an enhanced antioxidant pathway through stimulation of p62, Nrf2, and GSH, associated with reduced Keap1 and MDA. Moreover, ubiquinol decreased mTOR, thus enhanced autophagy markers viz. LC3-II. Furthermore, ubiquinol showed an antiapoptotic effect by enhancing Bcl-2 and reducing caspase-3 and Bax. Consequently, ubiquinol exerts a splenic-protective effect against irradiation via enhancing antioxidant, autophagic, and survival pathways.