Study Design. Experimental animal study investigating the efficacy of C-terminal domain of tetanus toxin application as neuroprotective effects on rat brain in a model of spinal cord injury (SCI). Objective. The aim of the present study was to investigate the possible role of C-terminal domain of tetanus toxin (Hc-TeTx) on cell death mechanisms including apoptosis and autophagy following SCI. Summary of Background Data. Traumatic SCI can lead to posttraumatic inflammation, oxidative stress, motor neuron apoptosis, necrosis, and autophagy of tissue. To promote and enhance recovery after SCI, recent development of devices and therapeutic interventions are needed. Methods. Twenty-eight adult rats were divided into four groups (n = 7 each) as follows: sham, trauma (SCI), SCI + Hc-TeTx, and SCI + methylprednisolone groups. The functional neurological deficits due to the SCI were assessed by behavioral analysis using the Basso, Beattie and Bresnahan (BBB) open-field locomotor test. The alterations in pro-/anti-apoptotic and autophagy related-protein levels were measured by Western blotting technique. Results. In this study, Hc-TeTx promotes locomotor recovery and motor neuron survival of SCI rats. Hc-TeTx also decreased expression of bax, bad, bak, cleaved caspase-3, Ask1, and autophagy-related proteins including Atg5 and LC3II in brain. Our study provides an evidence that cell death mechanisms play critical roles in SCI and that the nontoxic peptides including Hc-TeTx may exert protective effect and decrease cell death following SCI. Conclusion. Our preliminary findings suggest a possible therapeutic agent to improve survival after spinal cord trauma, but further analysis are still needed to evaluate the difference between acute and chronic injuries. Level of Evidence: N/A

As the source of several anticancer drugs, the marine environment is a treasure trove for the discovery of new drugs. In this study, a sesterterpenoid-type natural product heteronemin was investigated as a potential ferroptotic agent in the pancreatic cancer cell line (Panc-1). The effect of heteronemin on lipid peroxidation and autophagy- and ferritin-related protein expressions was examined using spectrophotometric and immunoblotting techniques, respectively. As well, several preclinical cell-based tests were used for the anticancer assessment. Results: Heteronemin at 55 nM concentration reduced cell viability by 50%. Heteronemin-induced cell death was reversed by a ferroptosis inhibitor, Ferrostatin-1. The levels of ferroptosis markers and malondialdehyde (MDA) were upregulated by heteronemin treatment while glutathione peroxidase-4 (GPX4) protein expression was downregulated. Also, significant alterations in ferritinophagy- and iron-related proteins (Atg5, Atg7, FTL, STEAP3, and DMT-1) were observed in Panc-1 cells (p < 0.05). Conclusions: The obtained results indicated that heteronemin exerted its pharmacological effect via triggering ferroptosis in pancreatic cancer. The potent cytotoxic effect of heteronemin suggested its potential development as a drug lead in the war against cancer.

Programmed cell death (apoptosis) is mainly responsible for neuronal damage in neurodegenerative diseases. Thus, inhibition of apoptosis could represent an effective strategy in the prevention of these diseases. In this study, we aimed to compare the apoptotic responses of neurotoxins that are widely used to induce neuronal damage in cell culture studies and help to decide the most suitable experimental model for drug studies that target apoptosis. Cell viability analyses were performed by MTT assay following 1-methyl-4-phenylpyridinium (MPP +), 6-hydroxydopamine (6-OHDA), rotenone and paraquat treatments at three different time points (12, 24, 48h). Pro-apoptotic (Bax, Bad, Bak), anti-apoptotic (Bcl-2, Bcl-xl) protein levels and total caspase-3 protein levels were determined by Western Blotting technique following treatments. As expected, all neurotoxins managed to trigger cell death and apoptotic pathway. On the other hand, each neurotoxin was found to enhance and/or reduce the levels of different proteins that are associated with apoptosis. Due to different responses of apoptosis related proteins to neurotoxins, it can be concluded that the determination of target proteins with a number of protein-binding assays prior to cell culture studies and then deciding an in vitro model are essential while screening newly synthesized drugs that target apoptosis.

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