Scorpion venom peptide HsTx2 suppressed PTZ-induced seizures in mice via the circ_0001293/miR-8114/TGF-β2 axis

Abstract

Background Due to the complexity of the mechanisms involved in epileptogenesis, the available antiseizure drugs (ASDs) do not meet clinical needs; hence, both the discovery of new ASDs and the elucidation of novel molecular mechanisms are very important. Methods BALB/c mice were utilized to establish an epilepsy model induced by pentylenetetrazol (PTZ) administration. The peptide HsTx2 was administered for treatment. Primary astrocyte culture, immunofluorescence staining, RNA sequencing, identification and quantification of mouse circRNAs, cell transfection, bioinformatics and luciferase reporter analyses, enzyme-linked immunosorbent assay, RNA extraction and reverse transcription–quantitative PCR, Western blot and cell viability assays were used to explore the potential mechanism of HsTx2 via the circ_0001293/miR-8114/TGF-β2 axis. Results The scorpion venom peptide HsTx2 showed an anti-epilepsy effect, reduced the inflammatory response, and improved the circular RNA circ_0001293 expression decrease caused by PTZ in the mouse brain. Mechanistically, in astrocytes, circ_0001293 acted as a sponge of endogenous microRNA-8114 (miR-8114), which targets transforming growth factor-beta 2 (TGF-β2). The knockdown of circ_0001293, overexpression of miR-8114, and downregulation of TGF-β2 all reversed the anti-inflammatory effects and the influence of HsTx2 on the MAPK and NF-κB signaling pathways in astrocytes. Moreover, both circ_0001293 knockdown and miR-8114 overexpression reversed the beneficial effects of HsTx2 on inflammation, epilepsy progression, and the MAPK and NF-κB signaling pathways in vivo. Conclusions HsTx2 suppressed PTZ-induced epilepsy by ameliorating inflammation in astrocytes via the circ_0001293/miR-8114/TGF-β2 axis. Our results emphasized that the use of exogenous peptide molecular probes as a novel type of ASD, as well as to explore the novel endogenous noncoding RNA-mediated mechanisms of epilepsy, might be a promising research area. Graphical Abstract

Current Status of Peptide Medications and the Position of Active Therapeutic Peptides with Scorpion Venom Origin

“…Medicinal compounds identified in scorpion venoms have diverse abilities. They can target a wide range of diseases, including cardiovascular disorders, epilepsy (37), autoimmune problems (38), hypertension (39), cancers (36,37), pain (40), as well as inflammatory (41) and microbial diseases (42-44) (Figure 1).…”

Harnessing the Power of Venomous Animal-Derived Toxins against COVID-19

“…The synthetic peptide HsTx2 was demonstrated to reduce TNF-α, IFN-γ, and IL-6 levels in BALB/c mice [ 83 ]. This molecule is based on peptide HsTx2 from the Heterometrus spinifer scorpion venom, and it presented neuroprotective effects in rats during ischemic stroke [ 84 ].…”

A short peptide exerts neuroprotective effects on cerebral ischemia–reperfusion injury by reducing inflammation via the miR-6328/IKKβ/NF-κB axis

“…Active peptides Hi1a from Australian funnel-web spider Hadronyche infensa and exendin-4 from Heloderma suspectum venom have been found to have an anti-stroke activity, effectively alleviating the recovery of non-penumbra after stroke and improving prognosis [ 32 , 33 ]. Despite this, research on the treatment of ischemic encephalopathy with peptide drugs remains poor, and the inhibition of inflammation and neuroprotective effects of peptides need further exploration [ 34 ]. Amphibians are a natural treasure trove of bioactive peptides, with their skin and skin secretions containing structurally rich bioactive peptides, with antibacterial, antioxidant, and anti-inflammatory activities [ 30 , 35 ].…”