Increasing evidence in both experimental and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of both types of diabetes mellitus. Free radicals are formed disproportionately in diabetes by glucose oxidation, nonenzymatic glycation of proteins, and the subsequent oxidative degradation of glycated proteins. Abnormally high levels of free radicals and the simultaneous decline of antioxidant defense mechanisms can lead to damage of cellular organelles and enzymes, increased lipid peroxidation, and development of insulin resistance. These consequences of oxidative stress can promote the development of complications of diabetes mellitus. Changes in oxidative stress biomarkers, including superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, glutathione levels, vitamins, lipid peroxidation, nitrite concentration, nonenzymatic glycosylated proteins, and hyperglycemia in diabetes, and their consequences, are discussed in this review. In vivo studies of the effects of various conventional and alternative drugs on these biomarkers are surveyed. There is a need to continue to explore the relationship between free radicals, diabetes, and its complications, and to elucidate the mechanisms by which increased oxidative stress accelerates the development of diabetic complications, in an effort to expand treatment options.

Diabetes, oxidative stress, and antioxidants: a review

Peroxynitrite--the product of the diffusion-controlled reaction of nitric oxide with superoxide radical--is a short-lived oxidant species that is a potent inducer of cell death Conditions in which the reaction products of peroxynitrite have been detected and in which pharmacological inhibition of its formation or its decomposition have been shown to be of benefit include vascular diseases, ischaemia-reperfusion injury, circulatory shock, inflammation, pain and neurodegeneration In this Review, we first discuss the biochemistry and pathophysiology of peroxynitrite and then focus on pharmacological strategies to attenuate the toxic effects of peroxynitrite These include its catalytic reduction to nitrite and its isomerization to nitrate by metalloporphyrins, which have led to potential candidates for drug development for cardiovascular, inflammatory and neurodegenerative diseases

Peroxynitrite: biochemistry, pathophysiology and development of therapeutics

This review is focused on purinergic neurotransmission, i.e., ATP released from nerves as a transmitter or cotransmitter to act as an extracellular signaling molecule on both pre- and postjunctional membranes at neuroeffector junctions and synapses, as well as acting as a trophic factor during development and regeneration. Emphasis is placed on the physiology and pathophysiology of ATP, but extracellular roles of its breakdown product, adenosine, are also considered because of their intimate interactions. The early history of the involvement of ATP in autonomic and skeletal neuromuscular transmission and in activities in the central nervous system and ganglia is reviewed. Brief background information is given about the identification of receptor subtypes for purines and pyrimidines and about ATP storage, release, and ectoenzymatic breakdown. Evidence that ATP is a cotransmitter in most, if not all, peripheral and central neurons is presented, as well as full accounts of neurotransmission and neuromodulation in autonomic and sensory ganglia and in the brain and spinal cord. There is coverage of neuron-glia interactions and of purinergic neuroeffector transmission to nonmuscular cells. To establish the primitive and widespread nature of purinergic neurotransmission, both the ontogeny and phylogeny of purinergic signaling are considered. Finally, the pathophysiology of purinergic neurotransmission in both peripheral and central nervous systems is reviewed, and speculations are made about future developments.

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Physiology and Pathophysiology of Purinergic Neurotransmission

There are at least two types of cannabinoid receptors (CB1 and CB2). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ9-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptor more potently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB1, non-CB2 established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB1 and/or CB2 receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel “CB3” cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB1, non-CB2 pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB3 receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB1 receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB1/CB2 receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB1, non-CB2 cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.

https://pharmrev.aspetjournals.org/content/pharmrev/62/4/588.full.pdf

International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1 and CB2

▪ Abstract The neonicotinoids, the newest major class of insecticides, have outstanding potency and systemic action for crop protection against piercing-sucking pests, and they are highly effective for flea control on cats and dogs. Their common names are acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam. They generally have low toxicity to mammals (acute and chronic), birds, and fish. Biotransformations involve some activation reactions but largely detoxification mechanisms. In contrast to nicotine, epibatidine, and other ammonium or iminium nicotinoids, which are mostly protonated at physiological pH, the neonicotinoids are not protonated and have an electronegative nitro or cyano pharmacophore. Agonist recognition by the nicotinic receptor involves cation-π interaction for nicotinoids in mammals and possibly a cationic subsite for interaction with the nitro or cyano substituent of neonicotinoids in insects. The low affinity of neonicotinoids for vertebrate ...

NEONICOTINOID INSECTICIDE TOXICOLOGY: Mechanisms of Selective Action

Most insecticides are neurotoxicants causing various forms of hyperexcitation and paralysis in animals. A variety of neuroreceptors and ion channels have been identified as the major target sites of these neurotoxic insecticides. This paper gives the highlights of some of the recent development in this area. Pyrethroids keep the sodium channel open for unusually long times causing a prolonged flow of sodium current. The prolonged sodium current elevates and prolongs the depolarizing after-potential which reaches the threshold membrane potential to initiate repetitive after-discharges. We have developed the method with which the percentage of sodium channel population that needs to be modified to cause repetitive after-discharges can be measured accurately. In rat cerebellar Purkinje neurons, only 0.6% of sodium channels needs to be modified for hyperexcitation resulting in a large toxicity amplification. This concept is applicable to other neuroactive drugs that act through the threshold phenomenon. 'The mechanisms of selective toxicity of pyrethroids in mammals and insects have been quantitatively determined to be due mainly to the different sensitivity of the sodium channels to pyrethroids and the negative temperature dependence of pyrethroid action on the sodium channels. The degradation of pyrethroids play only a minor role. The negative temperature dependence of pyrethroid action is due to the increased sodium current flow at low temperature. The major site of action of dieldrin and hexachlorocyclohexane is the GABA A receptor chloride channel complex. Dieldrin exerts a dual action, initial stimulation and subsequent suppression, and the latter is responsible for hyperexcitation of animals. Dieldrin stimulation requires the γ2s subunit in the GABA receptor, whereas dieldrin suppression occurs in the presence or absence of the γ2s subunit.

Ion channels as targets for insecticides

Protective effect of boldine on oxidative mitochondrial damage in streptozotocin-induced diabetic rats

The effects of riluzole, a neuroprotective drug, on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) sodium channels in rat dorsal root ganglion neurons were studied using the whole-cell patch clamp technique. At the resting potential, riluzole preferentially blocked TTX-S sodium channels, whereas at more negative potentials, it blocked both types of sodium channels almost equally. The apparent dissociation constants for riluzole to block TTX-S and TTX-R sodium channels in their resting state were 90 and 143 μM, respectively. Riluzole shifted the voltage dependence of activation of TTX-R sodium channels in the depolarizing direction more than that of TTX-S sodium channels. The voltage dependence of the fast inactivation of both types of sodium channels was shifted in the hyperpolarizing direction in a dose-dependent manner, and the apparent dissociation constants for riluzole to block the inactivated channels were estimated to be 2 and 3 μM for the TTX-S and TTX-R sodium channels, respectively, indicating a much higher affinity for the inactivated channels than for the resting channels. Riluzole was equally effective in blocking both types of sodium channels in their slow inactivated state. Since more TTX-S channels are inactivated than TTX-R channels at the resting potential, riluzole blocks TTX-S sodium channels more potently than TTX-R sodium channels. It was concluded that one of the mechanisms by which riluzole exerts its neuroprotective action is to preferentially block the inactivated sodium channel of damaged or depolarized neurons under ischemic conditions, thereby suppressing excess stimulation of the glutamatergic receptors and massive influx of Ca++.

Differential Action of Riluzole on Tetrodotoxin-Sensitive and Tetrodotoxin-Resistant Sodium Channels

The effects of riluzole, a neuroprotective drug, on high voltage-activated (HVA) calcium channels of rat dorsal root ganglion neurons were studied using the whole-cell patch-clamp technique. Riluzole inhibited HVA calcium channel currents in a dose-dependent, time-dependent and reversible manner. The apparent dissociation constants for riluzole inhibition of the transient and sustained components of the current were 42.6 and 39.5 microM, respectively. Riluzole accelerated the activation kinetics of calcium channels without affecting the voltage dependence of activation. It accelerated the fast component of deactivation kinetics without affecting the slow component. It also accelerated fast and slow inactivation kinetics of the HVA channels. However, only one of the two components in the steady-state inactivation curve for the HVA channels was shifted in the hyperpolarizing direction by riluzole, which indicates differential block of the multiple-type HVA channels. By use of the specific blockers nimodipine, omega-conotoxin GVIA and omega-agatoxin IVA, the HVA calcium channels were found to comprise L-type (10%), N-type (63%), P/Q-type (23%) and R-type (9%). Riluzole blocked N- and P/Q-type channels, but not L-type channel, with the order of efficacy of P/Q- > N- >> L-type channels. Riluzole inhibition of N- and P/Q-type calcium channels may result in reduced calcium influx at presynaptic terminals, which thereby decreases excessive excitatory neurotransmitter release, especially glutamate, a mechanism known to cause neuronal death in ischemic conditions.

Effects of the Neuroprotective Agent Riluzole on the High Voltage-Activated Calcium Channels of Rat Dorsal Root Ganglion Neurons

The pyrethroid insecticides are known to slow the kinetics of the activation and inactivation gates of sodium channels. This results in prolonged openings of individual sodium channels and prolonged flow of whole-cell sodium current, which in turn cause hyperexcitation in animals. The aim of the present study was to solve three important remaining questions. First, the percentages of the sodium channels modified by the pyrethroid tetramethrin were measured and compared with the threshold concentration to initiate repetitive discharges in rat cerebellar Purkinje neurons. Tetramethrin at 0.1 microM modified only 0.6% of the sodium channels and generated repetitive afterdischarges. Thus, the pyrethroid toxicity is greatly amplified from the sodium channel to the whole animal. The pyrethroid sensitivity of Purkinje neuron sodium channels was lower than that of invertebrate sodium channels by a factor of > or = 10. Chloramine-T at 200 microM removed the sodium channel inactivation and increased the percentage of sodium channel modification by tetramethrin through open channel modification. Second, temperature had a profound effect on the ability of tetramethrin to cause repetitive afterdischarges; at 0.1 to 0.3 microM tetramethrin, repetitive discharges were induced at l5 degrees C and 20 degrees C, but this effect subsided at 25 degrees C to 35 degrees C. This negative temperature dependence could be explained by an increase in charge movement during slow tail current as temperature was lowered. The Q10 value for the charge movement during tail current was 0.22 between 20 degrees C and 30 degrees C. Third, the selective toxicity of pyrethroids between mammals and insects could be explained quantitatively on the basis of sodium channel factors that include temperature dependence, intrinsic sensitivity and recovery rate and detoxication factors.

Jin-Ho Song

Papers

Ion channels as targets for insecticides

Protective effect of boldine on oxidative mitochondrial damage in streptozotocin-induced diabetic rats

Differential Action of Riluzole on Tetrodotoxin-Sensitive and Tetrodotoxin-Resistant Sodium Channels

Effects of the Neuroprotective Agent Riluzole on the High Voltage-Activated Calcium Channels of Rat Dorsal Root Ganglion Neurons

Modulation of sodium channels of rat cerebellar Purkinje neurons by the pyrethroid tetramethrin.