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Neurotransmitter receptors play a vital role in the normal functioning of the nervous system. Controlled modulation of neurotransmitter receptors is critical for proper signaling between nerve cells and effector organs. Factors that disrupt normal neurotransmitter signaling can alter the homeostasis of the cells or tissues, leading to adverse effects. The release of neurotransmitters at the presynaptic neuron and the subsequent activation of postsynaptic receptors lead to stimulation or inhibition of neuronal transmission. The excitatory neurotransmission involves depolarization of the postsynaptic neuron or cell due to a decrease in the polarity of the cells by the influx of cations such as sodium ions. The excitatory neurotransmission is mainly carried out by glutamate receptors in the mammalian nervous system. The inhibitory neurotransmission is due to hyperpolarization of the cells by either influx of anions such as chloride ions or efflux of cations such as potassium ions. The GABA and glycine receptors serve as major inhibitory neurotransmitter receptors. Toxins and toxicants can interfere with neuronal transmission by directly binding receptors and modulating their function or by altering transmitter synthesis, release, and reuptake mechanisms. Therefore, neurotoxins can impair neuronal transmission at the synapse by either presynaptic modulation or postsynaptic modifications. Due to the intricate network of the nervous system, impairment of the receptor functions in the synapse can lead to regional network dysfunction, eventually resulting in adverse cellular effects and behavioral deficits. Therefore, a thorough knowledge of neurotransmitter receptor modulation by toxins and toxicants is essential for future development of therapies against adverse effects of these neurotoxic substances.

The transport of ions across biological membranes, via ion channels, is a critical event that regulates signal transduction, ionic homeostasis, and other cellular physiological and biochemical processes like the osmotic health of cells, providing nutritional requirements, and maintaining electrogenic gradients. Ion channels are integral pore-forming membrane proteins that are activated by changes in membrane voltage or by binding of specific ligands. Specific binding sites on ion channels are also modulatory targets for a variety of toxic compounds, which affect ion channel function resulting in deleterious toxicological effects. Several toxins that target one specific subtype of ion channels have been isolated from a variety of plants, invertebrates, and vertebrates. Voltage-gated sodium channels are ubiquitously expressed in several cell types. The classification of toxins is based on toxin-specific binding sites. Sodium channel physiology and toxicology have been extensively researched, and the major types of toxins that modulate these channels include tetrodotoxin, saxitoxin, scorpion toxins, spider toxins, sea anemone toxins, and pyrethroids. The potassium channels show great variation in terms of their genetic diversity and channel properties. The major toxins that modulate potassium channels include scorpion toxins and dendrotoxins. The voltage-gated calcium channels are classified based upon their voltage threshold for activation and channel properties and are affected by toxins such as ω-conotoxins, ω-agatoxins, huwenotoxins, and glycerotoxin. Chloride channels are inhibited by Georgia anion toxin and are different from the ligand-gated γ-aminobutyric acid (GABA) and glycine receptors. GABA receptors are well characterized in terms of toxicology and are prominent targets of certain insecticides. The ionotropic glutamate receptors are one class of ligand-gated receptors that are affected by heavy metal ions and toxins, both synthetic and natural. The other major types of receptors include acetylcholine receptors and serotonin receptors; the former are targets of peptide toxins from venoms and the latter are targets of abused drugs of plant origin. The ion channel toxins, especially the ones with high binding affinities, have served as valuable tools for elucidating the structure and function of various ion channels. In addition, the knowledge of ion channel modulations by toxins serves as a basis for the future development of effective therapies. This chapter provides an updated systematic review of ion channel toxicology, particularly of the voltage-gated ion channels.

In this chapter, we describe the common molecular mechanisms of neurodegeneration and apoptosis underlying neural injury that results from traumatic brain injury, stroke, and Alzheimer’s disease. We also discuss the influence of the immune system on neural injury, and how estrogens may modulate apoptotic and neuroprotective pathways, as well as the immune response. Additionally, we review the evidence, from in vitro and in vivo studies, that describes the neuroprotective effects of estrogens against neurodegeneration resulting from neural injury. Finally, we discuss limitations and future directions needed to make estrogens a viable option for use in neural injury.