A selective neurotoxin takes many forms: as an antibody to a neurotrophin, as an alkylator, as an excitotoxin, as a blocker of requisite neuronal excitation during ontogenetic development, as a generator of oxidative stress, as an inhibitor of vital intraneuronal processes, and as an agent adversely affecting a host of multiple sites in neurons. Neurotoxins have been invaluable for elucidating cellular mechanisms attending or preventing neuronal necrosis and apoptosis, and for modeling and thereby discerning mechanisms invoked in neurological and psychiatric disorders. Neuroprotectants, endogenous and exogenous, are being explored as potentially useful agents to ward off diseases. Finally, hypothesized as posing a risk to humans as environmental constituents, neurotoxins are now being remodeled as adjuncts for therapeutic intervention in a variety of human medical disorders.

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) destroys dopamine-containing nigrostriatal neurons and increases the apparent Bmax of both D1 and D2 binding sites in the striatum. However, the changes of Bmax occur at different intervals after the lesion. Up-regulation of D2 sites becomes evident about 3 weeks after the lesion and lasts for about 3 months. In contrast, about 3 months are required for the up-regulation of D1 sites and increased binding is still evident after 5 months.

<p>Parkinson’s disease is a neurodegenerative disorder characterized by a loss of dopaminergic neurons, where mitochondrial dysfunction and neuroinflammation are implicated in this process. However, the exact mechanisms of mitochondrial dysfunction, oxidative stress and neuroinflammation leading to the onset and development of Parkinson’s disease are not well understood. There is a lack of tools necessary to dissect these mechanisms, therefore we engineered genetically encoded fluorescent biosensors to monitor redox status and an inflammatory signal peptide with high spatiotemporal resolution. To measure intracellular redox dynamics, we developed red-shifted redox sensors and demonstrated their application in dual compartment imaging to study cross compartmental redox dynamics in live cells. To monitor extracellular inflammatory events, we developed a family of spectrally diverse genetically encoded fluorescent biosensors for the inflammatory mediator peptide, bradykinin. At the organismal level, we characterized the locomotor effects of mitochondrial toxicant-induced dopaminergic disruption in a zebrafish animal model and evaluated a behavioral assay as a method to screen for dopaminergic dysfunction. Pairing our intracellular redox sensors and our extracellular bradykinin sensors in a Parkinson’s disease animal model, such as a zebrafish toxicant-induced model will prove useful for dissecting the role of mitochondrial dysfunction and inflammation in Parkinson’s disease. </p>

Over the past 60 years, a large number of selective neurotoxins were discovered and developed, making it possible to animal-model a broad range of human neuropsychiatric and neurodevelopmental disorders. In this paper, we highlight those neurotoxins that are most commonly used as neuroteratologic agents, to either produce lifelong destruction of neurons of a particular phenotype, or a group of neurons linked by a specific class of transporter proteins (i.e., dopamine transporter) or body of receptors for a specific neurotransmitter (i.e., NMDA class of glutamate receptors). Actions of a range of neurotoxins are described: 6-hydroxydopamine (6-OHDA), 6-hydroxydopa, DSP-4, MPTP, methamphetamine, IgG-saporin, domoate, NMDA receptor antagonists, and valproate. Their neuroteratologic features are outlined, as well as those of nerve growth factor, epidermal growth factor, and that of stress. The value of each of these neurotoxins in animal modeling of human neurologic, neurodegenerative, and neuropsychiatric disorders is discussed in terms of the respective value as well as limitations of the derived animal model. Neuroteratologic agents have proven to be of immense importance for understanding how associated neural systems in human neural disorders may be better targeted by new therapeutic agents.

Neurotoxlns represent unique chemical tools, providing a means to 1) gain insight into cellular mechanisms of apopotosis and necrosis, 2) achieve a morphological template for studies otherwise unattainable, 3) specifically produce a singular phenotype of denervation, and 4) provide the starting point to delve into processes and mechanisms of nerve regeneration and sprouting. There are many other notable uses of neurotoxins in neuroscience research, and ever more being discovered each year. The objective of this review paper is to highlight the broad areas of neuroscience in which neurotoxins and neurotoxicity mechanism come into play. This shifts the focus away from neurotoxins per se, and onto the major problems under study today. Neurotoxins broadly defined are used to explore neurodegenerative disorders, psychiatric disorders and substance use disorders. Neurotoxic mechanisms relating to protein aggregates are indigenous to Alzheimer disease, Parkinson's disease. NeuroAIDS is a disorder in which microglia and macrophages have enormous import. The gap between the immune system and nervous system has been bridged, as neuroinflammation is now considered to be part of the neurodegenerative process. Related mechanisms now arise in the process of neurogenesis. Accordingly, the entire spectrum of neuroscience is within the purview of neurotoxins and neurotoxicity mechanisms. Highlights on discoveries in the areas noted, and on selective neurotoxins, are included, mainly from the past 2 to 3 years.

Neurotoxins, in the general sense, represent novel chemical structures which when administered in vivo or in vitro, are capable of producing neuronal damage or neurodegeneration - with some degree of specificity relating to neuronal phenotype or populations of neurons with specific characteristics (.e., receptor type, ion channel type, astrocyte-dependence, etc.). The broader term 'neurotoxin' includes this categorization but extends the term to include intra- or extracellular mediators involved in the neurodegenerative event, including necrotic and apoptotic factors. Moreover, as it is recognized that astrocytes are essential supportive satellite cells for neurons, and because damage to these cells ultimately affects neuronal function, the term 'neurotoxin' might reasonably be extended to include those chemical species which also adversely affect astrocytes. This review is intended to highlight developments that have occurred in the field of 'neurotoxins' during the past 5 years, including MPTP/MPP+, 6-hydroxydopamine (6-OHDA), meth-amphetamine; salsolinol; leukoaminochrome-o-semi-quinone; rotenone; iron; paraquat; HPP+; veratridine; soman; glutamate; kainate; 3-nitropropionic acid; peroxynitrite anion; and metals (copper, manganese, lead, mercury). Neurotoxins represent tools to help elucidate intra- and extra-cellular processes involved in neuronal necrosis and apoptosis, so that drugs can be developed towards targets that interrupt the processes leading towards neuronal death.

La maladie de Parkinson (MP) est un trouble dégénératif du système nerveux central qui affecte principalement les personnes âgées. Son principal traitement est la L-3,4-dihydroxyphénylalanine (L-DOPA), qui malheureusement provoque des problèmes handicapants tels que les dyskinésies et les psychoses à la suite d’une administration chronique. Peu de traitements sont disponibles pour réduire efficacement ces complications et certains interfèrent avec l’effet thérapeutique de la L-DOPA, alors que d’autres induisent des effets secondaires potentiellement dangereux pour la vie des patients. Il est donc crucial de découvrir de nouvelles cibles thérapeutiques. Des études cliniques et précliniques ont montré que le site de liaison de la glycine du récepteur N-méthyl-D-aspartate (NMDA) est une cible thérapeutique prometteuse pour les problèmes moteurs de la MP. En effet, la stimulation de celui-ci augmenterait la transmission glutamatergique via la voie hyperdirecte des ganglions de la base, et par conséquent favoriserait l’inhibition du thalamus qui mènera à une moindre activation du cortex moteur, et donc possiblement moins de dyskinésies. De plus, puisque l’activation des récepteurs NMDA le long de la voie nigro-striée augmente la libération de dopamine dans le striatum, il est possible qu’un effet antiparkinsonien soit également obtenu. L’objectif de cette étude est de caractériser les potentiels anti-dyskinétique, antipsychotique et antiparkinsonien de l’inhibition sélective du transporteur de la glycine 1 (GlyT1) chez deux modèles animaux de la MP. Le chapitre 1 décrit le développement et la validation d’une nouvelle méthode de détection pour quantifier les niveaux plasmatiques du bitopertin, un inhibiteur du GlyT1. Le chapitre 2 détermine le profil pharmacocinétique du bitopertin chez le rat, à la suite d’une administration sous-cutanée. Le chapitre 3 évalue l’effet du bitopertin sur la dyskinésie et le parkinsonisme chez le rat hémi-parkinsonien, montrant une amélioration significative de la dyskinésie et du parkinsonisme. Le chapitre 4 évalue l’effet de l’ALX-5407, un inhibiteur du GlyT1, sur la dyskinésie et les comportements de types psychotiques chez le ouistiti lésé au 1-méthyl-4-phényl-1,2,3,6-tétrahydropyridine (MPTP), démontrant une amélioration de la sévérité globale de la dyskinésie, des comportements de type psychose et du parkinsonisme. Dans l’ensemble, ces résultats fournissent des données convaincantes pour soutenir le potentiel thérapeutique de l’inhibition de GlyT1. De plus, le bitopertin a fait l’objet d’essais cliniques approfondies pour le traitement de la schizophrénie, et a présenté un profil de sécurité et de tolérance bien documenté, ce qui en fait un candidat attrayant pour une nouvelle étude clinique dans le traitement de la MP. / Parkinson's disease (PD) is a degenerative disorder of the central nervous system that primarily affects older people. Its main treatment is L-3,4-dihydroxyphenylalanine (L-DOPA), which unfortunately causes disabling problems such as dyskinesias and psychosis following chronic administration. Few treatments are available to effectively reduce these complications, and some interfere with the therapeutic effect of L-DOPA, while others induce potentially life-threatening side effects. It is therefore crucial to discover new therapeutic targets. Clinical and preclinical studies have shown that the glycine site of the N-methyl-D-aspartate (NMDA) receptor is a promising therapeutic target for motor problems in PD. Indeed, this may increase glutamatergic transmission via the hyperdirect pathway of the basal ganglia, and consequently promote inhibition of the thalamus, which will lead to minimal activation of the motor cortex, and therefore possibly less dyskinesia. Additionally, since activation of NMDA receptors along the nigrostriatal pathway increases dopamine release in the striatum, it is possible that an antiparkinsonian effect is also achieved. The objective of this study is to characterize the anti-dyskinetic, antipsychotic and antiparkinsonian potentials of selective inhibition of glycine transporter 1 (GlyT1) in two animal models of PD. Chapter 1 describes the development and validation of a new detection method to quantify plasma levels of bitopertin, a GlyT1 inhibitor. Chapter 2 determines the pharmacokinetic profile of bitopertin in rats, following subcutaneous administration. Chapter 3 evaluates the effect of bitopertin on dyskinesia and parkinsonism in hemi-parkinsonian rats, showing a significant improvement in dyskinesia and parkinsonism. Chapter 4 evaluates the effect of ALX-5407, a GlyT1 inhibitor, on dyskinesia and psychotic-like behaviours in marmosets injured with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), demonstrating an improvement in the overall severity of dyskinesia, psychosis-like behaviours, and parkinsonism. Taken together, these results provide compelling data to support the therapeutic potential of GlyT1 inhibition. Additionally, bitopertin has been extensively tested in clinical trials for the treatment of schizophrenia, and has demonstrated a well-documented safety and tolerability profile, making it an attractive candidate for further clinical study in the treatment of the PD.

The era of selective neurotoxins arose predominately in the 1960s with the discovery of the norepinephrine (NE) isomer 6-hydroxydopamine (6-OHDA), which selectively destroyed noradrenergic sympathetic nerves in rats. A series of similarly selective neurotoxins were later discovered, having high affinity for the transporter site on nerves and thus being accumulated and able to disrupt vital intraneuronal processes, to lead to cell death. The Trojan Horse botulinum neurotoxins (BoNT) and tetanus toxin bind to glycoproteins on the neuronal plasma membrane, then these stealth neurotoxins are taken inside respective cholinergic or glycinergic nerves, producing months-long functional inactivation but without overtly destroying those nerves. The mitochondrial complex I inhibitor rotenone, while lacking total specificity, still destroys dopaminergic nerves with some selectivity; and importantly, results in the neural accumulation of synuclein-to model Parkinson’s disease (PD) in animals. Other neurotoxins target specific subtypes of glutamate receptors and produce excitotoxicity in nerves with that receptor population. The dopamine D2 receptor agonist quinpirole, termed a selective neurotoxin, produces a behavioral state replicating some of the notable features of schizophrenia, but without overtly destroying nerves. These processes, mechanisms or treatment-outcomes account for the means by which neurotoxins are classified as such, and represent some of the means by which neurotoxins as a group are able to destroy or functionally inactivate nerves; or replicate an altered neurological state. Selective neurotoxins have proven to be important in gaining insight into biochemical processes and mechanisms responsible for survival or demise of a nerve. Selective neurotoxins are useful also for animal modeling of human neural disorders such as PD, Alzheimer disease, attention-deficit hyperactivity disorder (ADHD), Lesch-Nyhan disease, tardive dyskinesia, schizophrenia and others. The importance of neurotoxins in neuroscience will continue to be ever more important as even newer neurotoxins are discovered.

There has been an awareness of nerve poisons from ancient times. At the dawn of the twentieth century, the actions and mechanisms of these poisons were uncovered by modern physiological and biochemical experimentation. However, the era of selective neurotoxins began with the pioneering studies of R. Levi-Montalcini through her studies of the neurotrophin "nerve growth factor" (NGF), a protein promoting growth and development of sensory and sympathetic noradrenergic nerves. An antibody to NGF, namely, anti-NGF - developed in the 1950s in a collaboration with S. Cohen - was shown to produce an "immunosympathectomy" and virtual lifelong sympathetic denervation. These Nobel Laureates thus developed and characterized the first identifiable selective neurotoxin. Other selective neurotoxins were soon discovered, and the compendium of selective neurotoxins continues to grow, so that today there are numerous selective neurotoxins, with the potential to destroy or produce dysfunction of a variety of phenotypic nerves. Selective neurotoxins are of value because of their ability to selectively destroy or disable a common group of nerves possessing (1) a particular neural transporter, (2) a unique set of enzymes or vesicular transporter, (3) a specific type of receptor or (4) membranous protein, or (5) other uniqueness. The era of selective neurotoxins has developed to such an extent that the very definition of a "selective" neurotoxin has warped. For example, (1) N-methyl-D- aspartate receptor (NMDA-R) antagonists, considered to be neuroprotectants by virtue of their prevention of excitotoxicity from glutamate receptor agonists, actually lead to the demise of populations of neurons with NMDA receptors, when administered during ontogenetic development. The mere lack of natural excitation of this nerve population, consequent to NMDA-R block, sends a message that these nerves are redundant - and an apoptotic cascade is set in motion to eliminate these nerves. (2) The rodenticide rotenone, a global cytotoxin that acts mainly to inhibit complex I in the respiratory transport chain, is now used in low dose over a period of weeks to months to produce relatively selective destruction of substantia nigra dopaminergic nerves and promote alpha-synuclein deposition in brain to thus model Parkinson's disease. Similarly, (3) glial toxins, affecting oligodendrocytes or other satellite cells, can lead to the damage or dysfunction of identifiable groups of neurons. Consequently, these toxins might also be considered as "selective neurotoxins," despite the fact that the targeted cell is nonneuronal. Likewise, (4) the dopamine D2-receptor agonist quinpirole, administered daily for a week or more, leads to development of D2-receptor supersensitivity - exaggerated responses to the D2-receptor agonist, an effect persisting lifelong. Thus, neuroprotectants can become "selective" neurotoxins; nonspecific cytotoxins can become classified as "selective" neurotoxins; and receptor agonists, under defined dosing conditions, can supersensitize and thus be classified as "selective" neurotoxins. More examples will be uncovered as the area of selective neurotoxins expands. The description and characterization of selective neurotoxins, with unmasking of their mechanisms of action, have led to a level of understanding of neuronal activity and reactivity that could not be understood by conventional physiological observations. This chapter will be useful as an introduction to the scope of the field of selective neurotoxins and provide insight for in-depth analysis in later chapters with full descriptions of selective neurotoxins.