Animal Toxins as Therapeutic Tools to Treat Neurodegenerative Diseases

Abstract

Neurodegenerative diseases affect millions of individuals worldwide. So far, no disease-modifying drug is available to treat patients, making the search for effective drugs an urgent need. Neurodegeneration is triggered by the activation of several cellular processes, including oxidative stress, mitochondrial impairment, neuroinflammation, aging, aggregate formation, glutamatergic excitotoxicity, and apoptosis. Therefore, many research groups aim to identify drugs that may inhibit one or more of these events leading to neuronal cell death. Venoms are fruitful natural sources of new molecules, which have been relentlessly enhanced by evolution through natural selection. Several studies indicate that venom components can exhibit selectivity and affinity for a wide variety of targets in mammalian systems. For instance, an expressive number of natural peptides identified in venoms from animals, such as snakes, scorpions, bees, and spiders, were shown to lessen inflammation, regulate glutamate release, modify neurotransmitter levels, block ion channel activation, decrease the number of protein aggregates, and increase the levels of neuroprotective factors. Thus, these venom components hold potential as therapeutic tools to slow or even halt neurodegeneration. However, there are many technological issues to overcome, as venom peptides are hard to obtain and characterize and the amount obtained from natural sources is insufficient to perform all the necessary experiments and tests. Fortunately, technological improvements regarding heterologous protein expression, as well as peptide chemical synthesis will help to provide enough quantities and allow chemical and pharmacological enhancements of these natural occurring compounds. Thus, the main focus of this review is to highlight the most promising studies evaluating animal toxins as therapeutic tools to treat a wide variety of neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, brain ischemia, glaucoma, amyotrophic lateral sclerosis, and multiple sclerosis.

Keywords: animal venom; excitotoxicity; neurodegenerative disease; neuroinflammation; neuronal death; toxins.

FIGURE 1

Neuroprotective mechanisms elicited by Phoneutria nigriventer venom. The venom of the spider Phoneutria nigriventer contains a mixture of toxins that affect ion channel function, decreasing neuronal cell death and ameliorating neurotransmission alterations. The PhTx3-1 toxin is capable of blocking transient outward K⁺ currents (KvI_A), improving behavioral parameters associated with memory. The PhTx4-5-5 toxin has neuroprotective activity against glutamate-induced excitotoxicity by blocking NMDA receptors. The PhTx3–3 and PhTx3–4 toxins block N- and P/Q-type voltage-dependent Ca²⁺ channels (VDCC), thus inhibiting Ca²⁺ influx, glutamate release and ROS formation.

FIGURE 2

Neuroprotective mechanisms triggered by bee venom in Parkinson’s disease mouse models. The administration of bee venom (BV) or its isolated compounds to different PD mouse models leads to decreased neurodegeneration by reducing oxidative stress, neuroinflammation and apoptosis. BV antioxidant effect is highlighted by its capacity to decrease the levels of reactive oxygen species (ROS), reduce lipid peroxides and restore the antioxidant pool of brain tissue by increasing both glutathione peroxidase (GSH) level and brain PON1 activity. Several studies indicate that BV anti-inflammatory effect is the main mechanism contributing to neuroprotection. BV directly binds to the mannose receptor on dendritic cells and promotes secretion of PGE2, which binds to type T lymphocyte prostaglandin E2 (EP2) receptor, leading to Foxp3 expression. Consequently, it promotes T regulatory lymphocytes (T reg) differentiation, which induces neuroinflammation suppression by decreasing the number and level of activation of both astrocytes and microglia. The shrinkage of inflammatory cells leads to decreased release of proinflammatory factors, such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1). BV also promotes neuroprotection by reducing apoptosis, as it decreases Bax gene expression levels, caspase-3 activation, and DNA fragmentation.