The recent positional cloning of the mouse ob gene and its human homology has provided the basis to investigate the potential role of the ob gene product in body weight regulation. A biologically active form of recombinant mouse OB protein was overexpressed and purified to near homogeneity from a bacterial expression system. Peripheral and central administration of microgram doses of OB protein reduced food intake and body weight of ob/ob and diet-induced obese mice but not in db/db obese mice. The behavioral effects after brain administration suggest that OB protein can act directly on neuronal networks that control feeding and energy balance.

https://science.sciencemag.org/content/sci/269/5223/546.full.pdf

Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks.

A method has been described for the study of the central effects produced by the intracerebral injection of drugs in the unanaesthetized mouse. The effects observed were in good agreement with those obtained after similar injections in cats, dogs and human beings. After intracerebral injection, drugs of diverse structure produced certain generalized effects: changes in positioning of the tail, stupor, hyperexcitability and tachypnoea. Both acetylcholine and methacholine produced an akinetic seizure and depression, but the latter compound also caused lacrimation and salivation. Atropine produced piloerection, increased sensitivity to sound and touch, clonic convulsions and scratching, whereas hexamethonium caused Parkinsonian-like muscle tremors and peripheral vasodilatation. After adrenaline, hyperexcitability, exophthalmos, stupor and death from pulmonary oedema were observed, but (+)-methylamphetamine produced only piloerection and exaggerated activity in response to sound and touch. Ergotamine caused a decreased sensitivity to sound and touch, micturition, and stupor, while ergometrine caused clonic convulsions, piloerection, defaecation and stupor.

/pdf/pharmacological-effects-produced-by-intracerebral-injection-3ffvgshwll.pdf

Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse

Peptides have been identified in mammalian brain that are considered to be endogenous agonists for the delta (enkephalins) and kappa (dynorphins) opiate receptors, but none has been found to have any preference for the mu receptor. Because morphine and other compounds that are clinically useful and open to abuse act primarily at the mu receptor, it could be important to identify endogenous peptides specific for this site. Here we report the discovery and isolation from brain of such a peptide, endomorphin-1 (Tyr-Pro-Trp-Phe-NH2), which has a high affinity (Ki = 360 pM) and selectivity (4,000- and 15,000-fold preference over the delta and kappa receptors) for the mu receptor. This peptide is more effective than the mu-selective analogue DAMGO in vitro and it produces potent and prolonged analgesia in mice. A second peptide, endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), which differs by one amino acid, was also isolated. The new peptides have the highest specificity and affinity for the mu receptor of any endogenous substance so far described and they may be natural ligands for this receptor.

A potent and selective endogenous agonist for the mu-opiate receptor.

http://csmres.co.uk/cs.public.upd/article-downloads/Synthetic-therapeutic-peptides-science-and-market.pdf

Synthetic therapeutic peptides: science and market.

This report provides a review of early and late effects of radiation in normal tissues and organs with respect to radiation protection. It was instigated following a recommendation in Publication 103 (ICRP, 2007), and it provides updated estimates of 'practical' threshold doses for tissue injury defined at the level of 1% incidence. Estimates are given for morbidity and mortality endpoints in all organ systems following acute, fractionated, or chronic exposure. The organ systems comprise the haematopoietic, immune, reproductive, circulatory, respiratory, musculoskeletal, endocrine, and nervous systems; the digestive and urinary tracts; the skin; and the eye. Particular attention is paid to circulatory disease and cataracts because of recent evidence of higher incidences of injury than expected after lower doses; hence, threshold doses appear to be lower than previously considered. This is largely because of the increasing incidences with increasing times after exposure. In the context of protection, it is the threshold doses for very long follow-up times that are the most relevant for workers and the public; for example, the atomic bomb survivors with 40-50years of follow-up. Radiotherapy data generally apply for shorter follow-up times because of competing causes of death in cancer patients, and hence the risks of radiation-induced circulatory disease at those earlier times are lower. A variety of biological response modifiers have been used to help reduce late reactions in many tissues. These include antioxidants, radical scavengers, inhibitors of apoptosis, anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, growth factors, and cytokines. In many cases, these give dose modification factors of 1.1-1.2, and in a few cases 1.5-2, indicating the potential for increasing threshold doses in known exposure cases. In contrast, there are agents that enhance radiation responses, notably other cytotoxic agents such as antimetabolites, alkylating agents, anti-angiogenic drugs, and antibiotics, as well as genetic and comorbidity factors. Most tissues show a sparing effect of dose fractionation, so that total doses for a given endpoint are higher if the dose is fractionated rather than when given as a single dose. However, for reactions manifesting very late after low total doses, particularly for cataracts and circulatory disease, it appears that the rate of dose delivery does not modify the low incidence. This implies that the injury in these cases and at these low dose levels is caused by single-hit irreparable-type events. For these two tissues, a threshold dose of 0.5Gy is proposed herein for practical purposes, irrespective of the rate of dose delivery, and future studies may elucidate this judgement further.

https://journals.sagepub.com/doi/pdf/10.1016/j.icrp.2012.02.001

ICRP PUBLICATION 118: ICRP Statement on Tissue Reactions and Early and Late Effects of Radiation in Normal Tissues and Organs – Threshold Doses for Tissue Reactions in a Radiation Protection Context

Pharmacology and Toxicology of the Rare Earth Elements

A study has been made of the toxicology and pharmacology of gadolinium and samarium chlorides. The symptoms of acute toxicity following intraperitoneal injection are described. The chronic oral ingestion of both chemicals for 12 weeks produced no effects on growth or the blood picture, and only the male rats receiving gadolinium chloride showed liver damage. The pharmacological responses to both chemicals were mainly depressant on all systems studied, and death was associated with cardiovascular collapse coupled with respiratory paralysis. The greatest damage seen was on abraded skin, where non-healing ulcers were produced by both chemicals, whereas irritation of intact skin and ocular tissues was only transient in nature.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1961.tb01139.x

Toxicological and pharmacological effects of gadolinium and samarium chlorides.

Specific alterations in spontaneous and evoked brain electrical activity were demonstrated in cats receiving 400 or 200 r of WBR or 400 r localized to the head or body. Results obtained in unrestrained cats with electrodes in the cortex and subcortex are reported. (C.H.)

Effects of X-Irradiation on Spontaneous and Evoked Brain Electrical Activity in Cats

It has been demonstrated that total-body X-irradiation activates the pituitaryadrenal axis as evidenced by the changes in the cholesterol and ascorbic acid content of the adrenal gland (1-6). Subsequently, by using hypophysectomized animals, Patt et al. (7) showed that the adrenal response was dependent on an intact pituitary. However, correlation between the plasma steroid levels and the adrenocorticotrophic activity in the pituitary or the peripheral blood after total-body X-irradiation are rendered difficult by the equivocal results reported by different workers (8-11). Mateyko and Edelmann (8) found the ACTH content in the rat pituitary to be increased at 1 hour after whole-body exposure to 1000 r, reaching the control levels within 6 hours, and to be subnormal at 24 hours. More recently, Binhammer and Crocker (11) showed a rapid decline in the pituitary ACTH activity in rats, reaching a minimum at 0.5 hour and returning to control levels at 24 hours after total-body X-irradiation with 1000 r. Direct quantitative estimations of plasma adrenocortical hormones after irradiation have given variable results. Larina and Sakhatskaya (12) found, in rats exposed to 650 r, a decline in the corticosterone concentrations in the suprarenal blood, which reached inestimable levels at 3 hours, exceeded the controls by 35 % at 24 hours, and returned to control levels on the second day. Eechaute et al. (13), on the other hand, reported a threefold rise in the plasma corticosterone concentration at 2.5 hours after total-body X-irradiation with 750 r in rats, the hormone levels being restored to control values at 24 hours. The present investigation was undertaken to determine the effect of X-irradiation

Thomas J. Haley

Papers

Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse

Pharmacology and Toxicology of the Rare Earth Elements

Toxicological and pharmacological effects of gadolinium and samarium chlorides.

Effects of X-Irradiation on Spontaneous and Evoked Brain Electrical Activity in Cats

Plasma and adrenal gland corticosterone levels after x-ray exposure in rats.