Neuroprotective Fragment C of Tetanus Toxin Modulates IL-6 in an ALS Mouse Model

Abstract

Neuroinflammation plays a significant role in amyotrophic lateral sclerosis (ALS) pathology, leading to the development of therapies targeting inflammation in recent years. Our group has studied the tetanus toxin C-terminal fragment (TTC) as a therapeutic molecule, showing neuroprotective properties in the SOD1G93A mouse model. However, it is unknown whether TTC could have some effect on inflammation. The objective of this study was to assess the effect of TTC on the regulation of inflammatory mediators to elucidate its potential role in modulating inflammation occurring in ALS. After TTC treatment in SOD1G93A mice, levels of eotaxin-1, interleukin (IL)-2, IL-6 and macrophage inflammatory protein (MIP)-1 alpha (α) and galectin-1 were analyzed by immunoassays in plasma samples, whilst protein expression of caspase-1, IL-1β, IL-6 and NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) was measured in the spinal cord, extensor digitorum longus (EDL) muscle and soleus (SOL) muscle. The results showed reduced levels of IL-6 in spinal cord, EDL and SOL in treated SOD1G93A mice. In addition, TTC showed a different role in the modulation of NLRP3 and caspase-1 depending on the tissue analyzed. In conclusion, our results suggest that TTC could have a potential anti-inflammatory effect by reducing IL-6 levels in tissues drastically affected by the disease. However, further research is needed to study more in depth the anti-inflammatory effect of TTC in ALS.

Therapeutic Assay with the Non-toxic C-Terminal Fragment of Tetanus Toxin (TTC) in Transgenic Murine Models of Prion Disease

“…Each mouse line was separated into two different groups: a control group (Tg338 n = 12; C57BL6 n = 6) and a treated group (Tg338 n = 12; C57BL6 n = 6). The treated group was intramuscularly inoculated with 1 µg of TTC recombinant protein [ 39 ] in the quadriceps muscle once a month, for 6 months, while the control group was intramuscularly inoculated with PBS following the same pattern. Groups were sex-balanced, with approximately half males and half females in all of them.…”

The C‐terminal fragment of the heavy chain of the tetanus toxin (Hc‐TeTx) improves motor activity and neuronal morphology in the limbic system of aged mice

“…The values show the mean ± SEM; Student's t test **p < .01 and ***p < .001 compared to vehicle group inhibits apoptosis and prevents the death of cerebellar granule neurons under stress conditions by activating TrkA and TrkB neurotrophin receptors and their signaling cascades (Chaib-Oukadour et al, 2004;Gil et al, 2001Gil et al, , 2003. Studies suggest that the Hc-TeTx fragment promotes the survival of cerebellum, striatum, the medial septum, Hp, and cortex neurons, by protecting them from death due to apoptosis, oxidative stress, and inflammation, which could be associated with an improvement in motor and cognitive function (Mendieta et al, 2009(Mendieta et al, , 2012Moreno-Galarza et al, 2018;Moreno-Martinez et al, 2020;Patricio-Martínez et al, 2016;Radenovic et al, 2014;Sanchez-Gonzalez et al, 2014). In this sense, the results suggest that Hc-TeTx improves brain function under aging conditions, demonstrated by improved locomotor activity.…”

“…In vitro studies indicate that Hc-TeTx activates the neurotrophins' receptors, promoting the signaling pathways of cell survival in neurons (Chaib-Oukadour et al, 2004;Gil et al, 2003;Herrando-Grabulosa et al, 2013). Also, this fragment stimulates the synthesis and release of neurotrophic factors, such as BDNF , and by itself, exerts neuroprotective or neurorestorative effects in neurodegenerative models of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and animal models of depression or cerebral ischemic Mendieta et al, 2009;Moreno-Igoa et al, 2012;Moreno-Martinez et al, 2020;Patricio-Martínez et al, 2016;Radenovic et al, 2014;Sanchez-Gonzalez et al, 2014).…”

“…Also, this fragment stimulates the synthesis and release of neurotrophic factors, such as BDNF (Getachew et al., 2019), and by itself, exerts neuroprotective or neurorestorative effects in neurodegenerative models of Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and animal models of depression or cerebral ischemic (Getachew et al., 2019; Getachew & Tizabi, 2019; Mendieta et al., 2009; Moreno‐Igoa et al., 2012; Moreno‐Martinez et al., 2020; Patricio‐Martínez et al., 2016; Radenovic et al., 2014; Sanchez‐Gonzalez et al., 2014). In vivo studies, the Hc‐TeTx fragment protects neuronal death against neurotoxins such as MPP+, 6‐hydroxydopamine (6‐OHDA), amyloid‐beta peptide (25–35), or methamphetamine, and the animals show motor and cognitive improvements (Mendieta et al., 2009, 2012, 2016; Patricio‐Martínez et al., 2016).…”

Structural flexibility of the tetanus neurotoxin revealed by crystallographic and solution scattering analyses

“…The ability of TeNT to specifically and effectively target the central nervous system (CNS) by retrograde axonal transport, and deliver its protease domain (LC) into the cytosol across the synaptic vesicle lumen, has raised interest in using TeNT as a delivery vehicle to transport drugs into neurons. Numerous applications have been performed using the receptor binding domain (H C ) of TeNT (TeNT/H C ), including the TeNT/H C -mediated anti-inflammatory effect in amyotrophic lateral sclerosis (ALS) ( Moreno-Martinez, 2020 ), a TeNT/H C -mediated tracer for the study of the structure and organization of the nervous system ( Kissa, 2002 , Maskos et al, 2002 ), TeNT/H C -mediated neuronal targeting of metabolic enzymes ( Dobrenis et al, 1992 ) and TeNT/H C -mediated delivery of neurotrophins ( Bordet et al, 2001 , Rind, 2005 , Payne et al, 2006 , Roux et al, 2006 ). The use of TeNT as a therapeutic tool requires the removal of its toxicity.…”