The clinical manifestations of Bothrops atrox envenoming involve local and systemic changes, among which edema requires substantial attention due to its ability to progress to compartmental syndromes and sometimes cause tissue loss and amputations. However, the impact of edema on the poisoned body’s system has not been explored. Thus, the present study aimed to explore the systemic pathological and inflammatory events that are altered by intraplantar injection of B. atrox venom in a mouse model through hematologic, lipidic, and shotgun proteomics analysis. Plasma samples collected showed a greater abundance of proteins related to complement, coagulation, lipid system, platelet and neutrophil degranulation, and pathways related to cell death and ischemic tolerance. Interestingly, some proteins, in particular, Prdx2 (peroxiredoxin 2), Hba (hemoglobin subunit alpha), and F9 (Factor IX), increased according to the amount of venom injected. Our findings support that B. atrox venom activates multiple blood systems that are involved in thromboinflammation, an observation that may have implications for the pathophysiological progression of envenomations. Furthermore, we report for the first time a potential role of Prdx2, Hba, and F9 as potential markers of the severity of edema/inflammation in mice caused by B. atrox.

The concept of pain encompasses a complex interplay of sensory and emotional experiences associated with actual or potential tissue damage. Accurately describing and localizing pain, whether acute or chronic, mild or severe, poses a challenge due to its diverse manifestations. Understanding the underlying origins and mechanisms of these pain variations is crucial for effective management and pharmacological interventions. Derived from a wide spectrum of species, including snakes, arthropods, mollusks, and vertebrates, animal venoms have emerged as abundant repositories of potential biomolecules exhibiting analgesic properties across a broad spectrum of pain models. This review focuses on highlighting the most promising venom-derived toxins investigated as potential prototypes for analgesic drugs. The discussion further encompasses research prospects, challenges in advancing analgesics, and the practical application of venom-derived toxins. As the field continues its evolution, tapping into the latent potential of these natural bioactive compounds holds the key to pioneering approaches in pain management and treatment. Therefore, animal toxins present countless possibilities for treating pain caused by different diseases. The development of new analgesic drugs from toxins is one of the directions that therapy must follow, and it seems to be moving forward by recommending the composition of multimodal therapy to combat pain.

Objective: This study aims to investigate morphological alterations caused by partial sciatic nerve ligation (PNL) and the efficacy of a moderate-intensity swimming training as therapeutic strategy for nerve regeneration. Methods: A number of 30 male adult mice were equally divided in control, 14 days after PNL (PNL 14 days), 42 days after PNL (PNL 42 days), 70 days after PNL (PNL 70 days) and 5-week exercise training after 7 days post-lesion (PNL trained 35 days) groups. PNL trained 35 days group began with a 10-min session for 3 days and this time was gradually increased by 10 min every three sessions until the animals had swum for 50 min per session. Morphoquantitative analysis was carried out to assess nerve regeneration in each group. Results: PNL 14 days group exhibited less degenerating signs than PNL 42 days group, where most post-lesion alterations were visualized. Nerve area and minimum diameter were significantly lower (p < 0.05) than control group. PNL 70 days group showed a greater degree of regenerating fibers and similar morphometric parameters to control group. PNL trained 35 days demonstrated signs of regeneration, reaching control group values in the morphometric analysis. Discussion: PNL promotes great histopathological changes, which became more visible at 42 post-injury days. A natural nerve-regeneration tendency was observed throughout time, as observed in PNL 70 days group; nevertheless, moderate swimming training was found to be a therapeutic resource for nerve regeneration, accelerating such process from a morphoquantitative perspective. Abbreviations: ANOVA: One-way analysis of variance; BDNF: Brain-derived neurotrophic factor; FGF-2: Fibroblast growth factor 2; GDNF: Glial cell line derived neurotrophic factor; IGF: Insulin-link growth factor; IL-1β: Interleukin-1β; NGF: Neural growth factor; PBS: Phosphate-buffered saline; PNL: Partial sciatic nerve ligation

Objective: Animal models of chronic pain have demonstrated that glial cells are promising target for development of analgesic drugs. However, preclinical studies on glial response under chronic pain conditions vary depending on the cellular markers, the species used, the experimental design and model. Therefore, we investigate the expression profile of GFAP and Iba-1 during the behavioral manifestation of sensory disorder in inflammatory and neuropathic pain models. Methods: the expression profile of fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule-1 (Iba-1) were quantitated in the spinal dorsal horn of Balb/C mice submitted to six models of chronic pain. Protein analysis was performed by western blot and the results colligated with pain-related behavior. Results: Using the same method to quantitate proteins we observed that while GFAP is upregulated after axotomy, partial nerve injury and cutaneous inflammation, its expression is not changed during muscle inflammation, non-inflammatory muscle pain, and in a viral-associated pain. Differently, Iba-1 is downregulated after axotomy but upregulated after partial lesion of peripheral nerve as well as after virus inoculation and during non-inflammatory muscle pain. Cutaneous and muscle inflammation induced no change in Iba-1 expression in the dorsal horn.In spite of a marked time-dependent variation in protein expression, mechanical allodynia was present at any time of all the models investigated. Discussion: Under distinct pain conditions, GFAP and Iba-1 expression is dependent on the origin of the stimulus, disease progression and tissue affected. Moreover, their expression and is not necessarily associated to the behavior manifestation of pain.

The uncontrolled production of the reactive oxygen species (ROS) generates oxidative stress and the development of chronic diseases, such as hypertension. Antioxidant enzymes can reduce the cellular level of ROS. Nuclear erythroid factor 2 (Nrf-2) favors the expression and activity of antioxidant enzymes. In hypertensive rats, Nrf-2 expresssion appears to be reduced in blood vessels and, consequently, it favors the oxidative stress and vascular dysfunction. Apocynin (APO) has been considered a new antioxidant drug. APO reduces blood pressure, decreases ROS production, and improves endothelial function in spontaneously hypertensive rats (SHR). We hypothesized that the role of Nrf-2 in vascular reactivity is altered in SHR and APO-treatment prevents this alteration. To test this hypothesis, we evaluated aorta reactivity to phenylephrine (PE) and acetylcholine (ACh), in the absence and presence of Brusatol, Nrf-2 inhibitor. We used aortas from normotensive Wistar rats and SHR, untreated or treated with APO. Brusatol increased the reactivity of the aortas from SHR to PE, but did not change the reactivity of Wistar rat aortas. In APO-treated SHR aortas, the effect of Brusatol was not observed. The vasodilator responses to ACh were not modified by Brusatol in aortas from normotensive or hypertensive rats, untreated or treated with APO. These results suggest that Nrf-2 is activated in the contractile response to PE. In SHR aortas, exacerbated generation of ROS induces the activation of Nrf-2. This suggestion is reinforced by the lack of Brusatol effect in APO-treated SHR aortas. As APO is an antioxidant drug, the reduction of ROS in vascular cells would not lead to Nrf-2 activation.