Selective neurotoxins, chemical tools to probe the mind: The first Thirty years and beyond

Kostrzewa, Richard M.

doi:10.1007/bf03033336

Cited by 16 publications

(5 citation statements)

References 205 publications

(75 reference statements)

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“…Neurotoxins, in a stricter sense, represent exogenous compounds that produce specific neuronal damage when given in relatively small amounts (Kostrzewa, 1999;Segura-Aguilar and Kostrzewa, 2004;. In a broader sense, endogenous substances can produce toxic effects when present at higher concentrations, like the overexcitation of glutamate receptors, which leads to excitotoxic injury in the nervous system (Smythies, 1999).…”

Section: Discussionmentioning

confidence: 99%

Effects of pituitary adenylate cyclase activating polypeptide (PACAP) on the PKA-bad-14-3-3 signaling pathway in glutamate-induced retinal injury in neonatal rats

et al. 2007

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The neuropeptide PACAP (pituitary adenylate cyclase activating polypeptide) and its receptors are widely expressed in the nervous system including the retina. PACAP has well-known neuroprotective effects in neuronal cultures in vitro and against different insults in vivo. Recently, we have shown that PACAP1-38 is neuroprotective against monosodium glutamate (MSG)-induced retinal degeneration. Studying the molecular mechanisms of this protection has revealed that PACAP1-38 stimulates anti-apoptotic mechanisms such as phosphorylation of ERK1/2 and inhibits pro-apoptotic signaling molecules such as JNK1/2, p38MAPK, caspase-3 and the translocation of mitochondrial cytochrome c and apoptosis inducing factor in glutamate-treated retinas in vivo. In the present study we investigated the effects of PACAP1-38 on a further signal transduction pathway possibly involved in the protective effect of intravitreal PACAP1-38 administration against apoptotic retinal degeneration induced by neonatal MSG treatment. The focus of the present study was the protein kinase A (PKA)-Bad-14-3-3 transduction pathway. In vivo MSG treatment led to a reduction in the levels of anti-apoptotic molecules (phospho-PKA phospho-Bad, Bcl-xL and 14-3-3 proteins) in the retina. Co-treatment with PACAP1-38 counteracted these effects: the level of phospho-PKA, phospho-Bad, Bcl-xL and 14-3-3 were increased. All effects of PACAP1-38 were inhibited by the PACAP antagonist PACAP6-38. In summary, our results show that PACAP1-38 activates the PKA-Bad-14-3-3 pathway which is inhibited by MSG treatment. Our results also provide new insights into the signaling mechanisms possibly involved in the PACAP-mediated anti-apoptotic effects.

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Section: Discussionmentioning

confidence: 99%

Effects of pituitary adenylate cyclase activating polypeptide (PACAP) on the PKA-bad-14-3-3 signaling pathway in glutamate-induced retinal injury in neonatal rats

et al. 2007

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“…Hundreds of compounds are known to exert neurotoxic effects when given in relatively small amounts or in abnormally high concentrations (Kostrzewa, 1999; Segura-Aguilar and Kostrzewa, 2004;. When administered during the perinatal period, a number of them are known to produce a delay or long-lasting impairment in neurobehavioral development, motor and cognitive functioning in newborn rats (Harry, 1998;Koehl et al, 2001;Beninger et al, 2002;Reddy et al, 2002;Archer et al, 2002;Kostrzewa et al, 2003;Palomo et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Changes in open-field activity and novelty-seeking behavior in periadolescent rats neonatally treated with monosodium glutamate

et al. 2007

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Monosodium glutamate (MSG) treatment of neonatal rodents leads to degeneration of the neurons in the arcuate nucleus, inner retinal layers and various other brain areas. It also causes various changes in the motor activity, sensory performance and learning abilities. We have previously shown that MSG treatment delays the appearance of some reflexes during neurobehavioral development and leads to temporary changes in reflex performance and motor coordination. Investigation of novelty-seeking behavior is of growing importance for its relationship with sensitivity to psychomotor stimulants. Perinatal administration of numerous toxic agents has been shown to influence novelty-seeking behavior in rats, but little is known about the influence of neonatal MSG treatment on the novelty-seeking behavior. The aim of the present study was to compare changes in locomotor, spontaneous exploratory and novelty-seeking behavior in periadolescent rats neonatally treated with MSG. Newborn rats were treated with 4 mg/g MSG subcutaneously on postnatal days 1, 3, 5, 7 and 9. Open-field behavior was tested at 2, 3, 4, 6 and 8 weeks of age. We found that MSG administration led to only temporary increases in locomotor behavior, which was more pronounced during the first few postnatal weeks, followed by a subtle hypoactivity at 2 months of age. Novelty-seeking was tested in four 5-min trials at 3 weeks of age. Trial 1 was in an empty open-field, two identical objects were placed in the arena during trial 2 and 3, and one of them was replaced to a novel object during trial 4. We found that the behavioral pattern of MSG-treated rats was the opposite in all tested signs in the novelty exploration test compared to control pups. In summary, our present study shows that neonatal MSG treatment leads to early temporary changes in the locomotor activity followed by hypoactivity at 2 months of age. Furthermore, MSG-treated rats show a markedly disturbed novelty-seeking behavior represented by altered activity when subjected to a novel object.

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“…Other neurotoxins were ultimately developed (Kostrzewa, ). Hans Baumgarten and colleagues developed 5,6‐ and 5,7‐dihydroxytryptamine to selectively destroy serotonergic nerves (Baumgarten et al, ; Baumgarten and Lachenmayer, ; Baumgarten and Lachenmayer, ).…”

Section: Development and Categorization Of Other Neurotoxins—researchmentioning

confidence: 99%

Evolution of Neurotoxins: From Research Modalities to Clinical Realities

Kostrzewa

2009

CP Neuroscience

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In the 1950s, the discovery of anti-nerve growth factor, an immunotoxin stunting sympathetic neural development, signaled the advent of neurotoxins as research modalities. Other selective neurotoxins were discovered in rapid succession. In the 1960s, 6-hydroxydopamine and 6-hydroxydopa were shown to destroy noradrenergic and dopaminergic nerves. Excitotoxins (glutamate, aspartate, and analogs) were discovered in the 1970s. DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] proved to be selective for noradrenergic destruction, while 5,6- and 5,7-dihydroxytryptamines were relatively selective for serotonin neurons. Additional neurotoxins were discovered, but it was MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) that predominated neurotoxicity research in the 1980s. Eventually, Clostridium botulinum neurotoxin (BoNT), discovered as a "poisonous" principle in the late 1800s, resurfaced in purified and standardized forms as a clinically useful drug. Neurotoxins represent chemical tools, useful not only for discerning neuronal mechanisms and animal modeling of neurological disorders, but also for their use in medicine and potential as treatments for medical disorders. This unit reviews the early discovery of neurotoxins, describes categories of neurotoxins, and finally characterizes their usefulness--first as research tools, and eventually as clinical therapeutic agents.

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Selective neurotoxins, chemical tools to probe the mind: The first Thirty years and beyond

Cited by 16 publications

References 205 publications

Effects of pituitary adenylate cyclase activating polypeptide (PACAP) on the PKA-bad-14-3-3 signaling pathway in glutamate-induced retinal injury in neonatal rats

Effects of pituitary adenylate cyclase activating polypeptide (PACAP) on the PKA-bad-14-3-3 signaling pathway in glutamate-induced retinal injury in neonatal rats

Changes in open-field activity and novelty-seeking behavior in periadolescent rats neonatally treated with monosodium glutamate

Evolution of Neurotoxins: From Research Modalities to Clinical Realities

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