The effects of afferent input and N-methyl-D-aspartate (NMDA) receptor activation on neurogenesis were examined in an intact system, the rat dentate gyrus, where neurons are naturally born in the adult. In the adult dentate gyrus, activation of NMDA receptors rapidly decreased the number of cells synthesizing DNA, whereas blockade of NMDA receptors rapidly increased the number of cells in the S phase identified with 3H-thymidine. Acute treatment with NMDA receptor antagonists increased the birth of neurons and increased the overall density of neurons in the granule cell layer. Lesion of the entorhinal cortex, the main excitatory afferent population to the granule neurons, also increased the birth of cells in the dentate gyrus. These results suggest that adult neurogenesis in the dentate gyrus of the rat is altered by afferent input, via NMDA receptors, and may be regulated naturally by endogenous excitatory amino acids.

https://www.jneurosci.org/content/jneuro/15/6/4687.full.pdf

Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus

This article provides a comprehensive review of hormesis, a dose-response concept that is characterized by a low-dose stimulation and a high-dose inhibition. The article traces the historical foundations of hormesis, its quantitative features and mechanistic foundations, and its risk assessment implications. The article indicates that the hormetic dose response is the most fundamental dose response, significantly outcompeting other leading dose-response models in large-scale, head-to-head evaluations. The hormetic dose response is highly generalizable, being independent of biological model, endpoint measured, chemical class, and interindividual variability. Hormesis also provides a framework for the study and assessment of chemical mixtures, incorporating the concept of additivity and synergism. Because the hormetic biphasic dose response represents a general pattern of biological responsiveness, it is expected that it will become progressively more significant within toxicological evaluation and risk assessment practices as well as have numerous biomedical applications.

http://www.drroyspencer.com/wp-content/uploads/Calabrese-SETAC-2008.pdf

Hormesis: why it is important to toxicology and toxicologists.

A comprehensive review of pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists is presented. The therapeutic benefits of achieving receptor subtype selectivity are outlined and applications in the treatment of Alzheimer’s disease are discussed. A selection of chemical routes are described, which illustrate contemporary methodology for the synthesis of chiral medicinal compounds (asymmetric synthesis, chiral pool, enzymes). Routes to bicyclic intrannular amines and intramolecular Diels-Alder reactions are highlighted.

/pdf/muscarinic-receptor-agonists-and-antagonists-42ieyp1wi3.pdf

Muscarinic Receptor Agonists and Antagonists

Piracetam and other structurally related nootropics

The present article represents a comprehensive effort to assess the hypothesis that hormesis is a highly generalizable biological phenomenon independent of environmental stressor, biological endpoint, and experimental model system. The evaluative methodology and complementary approaches employed to assess this question are (1) evolutionary biology-based theoretical paradigm; (2) evaluation of > 20,000 toxicology articles using a priori entry and evaluative criteria; (3) evaluation of 17 large-scale studies each providing data on numerous agents tested in the same experimental model by the same research team; (4) the assimilation of experimental pharmacological data on 24 receptor systems in which biphasic dose responses have been established reproducibly along with hormetic mechanism elucidation; and (5) assessment of the original hormesis database with 1600 dose-response relationships demonstrating evidence consistent with the hormesis hypothesis. The complementary approaches for assessing hormesis provided strong support for its credibility as a central biological theory based on its high frequency of occurrence and quantitative features of expression within microbe, plant, and invertebrate and vertebrate animal systems. The findings suggest that hormetic effects represent evolutionary-based adaptive responses to environmentally induced disruptions in homeostasis. Such adaptive responses, which are incorporated into organismal integrative physiological systems and now clarified at the mechanistic level for more than two dozen receptor systems, provide a cogent basis for the application of hormetic mechanisms in the elucidation of fundamental evolutionary-based biological processes and in the development of novel clinical modalities.

Hormesis: a generalizable and unifying hypothesis.

A series of dihydro-1H-pyrrolizine-3,5(2H,6H)-diones were synthesized and evaluated for their ability to reverse electroconvulsive shock (ECS) induced amnesia in mice. Among the structure-activity relationships explored were the effects of ring size, the presence of heteroatoms (sulfur) in the ring system, and the introduction of alkyl substituents. The optimal ring size for the bicyclic system was 5.5 with dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (3), although some activity was present in the corresponding 5.6 [hexahydro-3,5-indolizinedione (7)] and 6.6 [tetrahydro-2H-quinolizine-4,6(3H,7H)-dione (9)] analogues. Replacement of the C-1 carbon atom in compound 3 with a sulfur [dihydropyrrolo[2,1-b]thiazole-3,5(2H,6H)-dione (10)] abolished activity, and the introduction of methyl groups resulted in poorer biological profiles except when the substitution was made at the 7a position [dihydro-7a-methyl-1H-pyrrolizine-3,5(2H,6H)-dione (4)]. In several instances, hydrolysis of the parent bicyclic compound was carried out to furnish the corresponding lactam acids, which were further derivatized. Several exhibited interesting activity, especially the 5-oxo-2-pyrrolidinepropanoic acid derivatives such as 5-oxo-2-pyrrolidinepropanoic acid (12), 5-oxo-2-pyrrolidinepropanoic acid phenylmethyl ester (17), 5-oxo-2-pyrrolidinepropanoic acid (3-chlorophenyl)methyl ester (20), N-4-pyridyl-5-oxo-2-pyrrolidinepropanoic acid amide (25), and N-(2,6-dimethylphenyl)-5-oxo-2-pyrrolidinepropanoic acid amide (27). Compound 3 (CI-911; rolziracetam) was also observed to improve performance on a delayed-response task in aged rhesus monkeys and was selected for evaluation in cognitively impaired human subjects on the basis of its biological profile and a wide margin of safety in animals.

Amnesia-reversal activity of a series of cyclic imides.

A series of 3-(aryloxy)pyridines was found to possess activity in enhancing retention for passive avoidance learning in mice. This test was used to select compounds with potential therapeutic properties for the treatment of cognitive disorders. Reference drugs that gave positive results in this procedure included d-amphetamine, magnesium pemoline, methyl phenidate, picrotoxin, phenytoin, and ethosuximide. All active compounds gave inverted U-shaped dose-response curves. The most active compounds of the 3-(aryloxy)pyridines included 3-phenoxypyridine (1), 3-(2-fluorophenoxy)pyridine (2), 3-(4-fluorophenoxy)pyridine (4), 3,3'-oxybis(pyridine) (23), and 3,3'-oxybis(pyridine) 1-oxide (24). 3-Phenoxypyridine (1) was clearly superior to all of the analogues tested in terms of the level of retention, grammometric potency, and the breadth of its inverted U-shaped dose-response curve. It was given the designation of CI-844 and after a detailed study of its pharmacological profile was submitted for preclinical toxicology.

Cognition-activating properties of 3-(aryloxy)pyridines

A number of peptides and modified peptides were synthesized and studied for their ability to reverse electroconvulsive shock-induced amnesia in rodents. A few of these peptides were selected for secondary evaluation in tests of short-term memory in rats and aged rhesus monkeys. A number of the peptides and modified peptides were active in the amnesia reversal test. In selected secondary tests, however, the chosen compounds failed to show significant activity in enhancing memory. New methods for preparing methyleneamino and methyleneoxy isosteres of peptides are reported. Other modified peptides also included methylenethio, methylenesulfonyl, and ethylene isosteres in place of the normal peptide amide bond.

Modified di- and tripeptides of the C-terminal portion of oxytocin and vasopressin as possible cognition activation agents.

A series of N-[(dialkylamino)alkyl]-2-oxo-1- pyrrolidineacetamides was synthesized. The title compounds reversed electroconvulsive shock (ECS) induced amnesia in mice when administered subsequent to the ECS treatment and were inactive in a general observational test for central nervous system (CNS) activity. Active compounds exhibited an inverted U-shaped dose-response curve. Among the compounds with the broadest dose-response curve, as well as the most potent, were those with the N-[2-[bis(1-methylethyl)amino] ethyl] or 2,6- dimethylpiperidinoethyl residues as amide substituent. The N-(dialkylamino) substituent markedly enhances amnesia-reversal activity, with ethylene providing the optimal chain length. N-[2-[Bis(1-methylethyl)amino]ethyl] -2-oxo-1- pyrrolidineacetamide N-(dialkylamino) substituent was selected for preclinical toxicological evaluation, assigned the investigational number CI-879 and the U.S. adopted name ( USAN ) pramiracetam . Pramiracetam demonstrated a wide margin of safety in animals and was well tolerated in normal human volunteers. It has shown encouraging activity in an open label trial in patients with primary degenerative dementia (PDD or senile dementia of the Alzheimer's type).

John G. Marriott

Papers

Amnesia-reversal activity of a series of cyclic imides.

Cognition-activating properties of 3-(aryloxy)pyridines

Modified di- and tripeptides of the C-terminal portion of oxytocin and vasopressin as possible cognition activation agents.

Amnesia-reversal activity of a series of N-[(disubstituted-amino)alkyl] -2-oxo-1-pyrrolidineacetamides, including pramiracetam.

Water-maze learning and effects of cholinergic drugs in mouse strains with high and low hippocampal pyramidal cell counts