The Blood-Brain Barrier in Infectious Diseases Its Permeability to Toxins in Relation to Their Electrical Charges

Friedemann, Ulrich; Elkeles, A.

doi:10.1016/s0140-6736(00)92558-3

Cited by 29 publications

(3 citation statements)

References 17 publications

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“…It has been known for >60 years that the injection of cationic molecules results in an increase in the permeability of cerebral vessels (Friedemann and Elkeles, 1934). Polycationic protamine sulfate, cationized ferritin, poly-L-lysine, and sulfated dextrans have all been shown to increase the permeability of horseradish peroxidase in rat brain (Nagy et al, 1981(Nagy et al, , 1983Vorbrodt et al, 1981;Hardebo and Kâhrström, 1985;Hart et al.…”

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confidence: 99%

Polyamine Modification Increases the Permeability of Proteins at the Blood‐Nerve and Blood‐Brain Barriers

Poduslo

Curran

1996

Journal of Neurochemistry

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The permeability of the blood‐nerve barrier (BNB) and the blood‐brain barrier (BBB) to superoxide dismutase (SOD), insulin, albumin, and IgG in normal adult rats was quantified by measuring the permeability coefficient‐surface area product (PS) with the intravenous bolus injection technique before and after covalent protein modification with the naturally occurring polyamines—putrescine (PUT), spermidine (SPD), and spermine (SPM). The PS value of the BNB for PUT‐SOD was 21.1‐fold greater than the native SOD, and the PS values of the BBB for PUT‐SOD ranged from 17.6‐fold greater for the thalamus to 23.6‐fold greater for the caudate‐putamen compared with native SOD. In a similar manner, polyamine‐modified insulin showed a 1.7–2.0‐fold increase in PS of the BNB and BBB compared with the high values of native insulin. Polyamine‐modified albumin showed a remarkable 54–165‐fold increase in PS of the BNB and BBB compared with native albumin, whereas PUT‐IgG resulted in an even higher increase in the PS that ranged from 111‐ to 349‐fold for nerve and different brain regions compared with native IgG. Polyamine modification of proteins, therefore, can dramatically increase the permeability at the BNB and BBB of a variety of proteins with widely differing Mr and function. It is surprising that the PS values of the BNB and BBB decreased with the increasing number of positive charges of the protonated amino groups on the polyamines (PUT > SPD > SPM). Although cationic proteins are known to interact with fixed anionic charges on the lumen of the microvascular endothelium, this observation of decreased permeability with increased positive charge distribution along the aliphatic carbon chain of the polyamines implies mechanisms other than simple electrostatic interaction involving charge density. It is suggested that the polyamine transporter may be responsible for the transport of these polyamine‐modified proteins. Systemic administration of polyamine‐modified peptides and proteins might prove to be an efficient approach to deliver therapeutic agents into the CNS and PNS for the treatment of a variety of neurological diseases.

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confidence: 99%

Polyamine Modification Increases the Permeability of Proteins at the Blood‐Nerve and Blood‐Brain Barriers

Poduslo

Curran

1996

Journal of Neurochemistry

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“…MacCallum (1914), however, showed that myocardial weakness is not primarily responsible for death in diphtheria intoxication. The other possibility, namely the paralysis of the vasomotor centre leading to circulatory failure, has been discussed and rejected by Friedemann & Elkeles (1934) and by the experimental work of Porter & Pratt (1914). Furthermore, one of us (S. C.…”

Section: Discussionmentioning

confidence: 99%

“…None of them have been entirely satisfactory. Some workers, Romberg, Pdssler, Briihns & Muller (1899), and Yabe (1922) thought it was due to the effect of toxin on the vasomotor centre, whereas others, Brodie (1899), Harding (1920), Myers (1933), and Friedemann & Elkeles (1934) considered that it was due to a direct effect on the peripheral blood vessels. Porter & Pratt (1914) found no evidence for malfunction of the vasomotor centre in diphtheria intoxication, and MacCallum (1914) reported that the toxin had no effect on the working capacity of the heart.…”

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Some peripheral actions of diphtheria toxin

Agarwal¹,

Nasmyth²

1959

The Journal of Physiology

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There have been many attempts to ascertain the mechanism of the circulatory failure in diphtheria intoxication. None of them have been entirely satisfactory. Some workers, Romberg, Pdssler, Briihns & Muller (1899), and Yabe (1922) thought it was due to the effect of toxin on the vasomotor centre, whereas others, Brodie (1899), Harding (1920), Myers (1933), andFriedemann &Elkeles (1934) considered that it was due to a direct effect on the peripheral blood vessels. Porter & Pratt (1914) found no evidence for malfunction of the vasomotor centre in diphtheria intoxication, and MacCallum (1914) reported that the toxin had no effect on the working capacity of the heart. In a few experiments in cats we have determined that the circulatory failure does not occur until the terminal stages of intoxication, and that when it does occur, death intervenes very shortly afterwards. The interval is so short that direct observations on the effects of the toxin on the circulatory system are not practicable. It probably also accounts for the conflicting views of the earlier workers. Agarwal & Holt (1959) analysed the positive Schick reaction obtained by injecting diphtheria toxin intradermally into guinea-pigs and showed that the skin vessels become refractory to adrenaline and noradrenaline in the Schick areas. They thought that the toxin may be acting on the smooth-muscle cells of the arterioles and capillaries. Hence they tested the effects of diphtheria toxin on another plain muscle, namely rabbit iris. The response of this muscle to doses of adrenaline was also depressed.The present study was undertaken to get a better understanding of the effects of diphtheria toxin on other plain muscles such as the nictitating membrane of the cat and the uterus of the rabbit. In an attempt to ascertain the mechanism by which diphtheria toxin decreases the excitability of muscles, we studied its effect on the loss of potassium from isolated guinea-pig auricles and from the rabbit uterus. We also investigated the differences in the electrolyte content ofvarious tissues in normal and diphtheria-intoxicated guinea-pigs.

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Charge dependence of the distribution of contrast agents in rat cerebral ventricles

Wan

London

1992

Magnetic Resonance in Med

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Previous studies of MRI contrast resulting from the intracerebral administration of several contrast agents have suggested that the distribution of these agents may be dependent on the net charge. In order to further evaluate the significance of this parameter, the distribution of both aquo and CDTA-chelated lanthanide and transition metal ions in the cerebral ventricles of rats has been evaluated based on their enhancement of MRI contrast. The agents were injected directly into the lateral ventricles of Sprague-Dawley rats. Each of five different positively charged paramagnetic metal ions tested selectively enhanced the inner cellular layers of ventricular luminal wall of the rat brain, while such enhancement was absent using the corresponding negatively charged metal-CDTA complexes. The abundance of negatively charged residues on the cell surface of the inner luminal layers is suggested to be the source of the observed charge affinity. Differences in the distribution of Mn2+ ions administered intracerebrally compared with intraperitoneal (ip) injection suggest that while the first treatment may result primarily in uncomplexed aquo ions which then interact with the luminal surface, manganese ions administered ip behave more like chelated ions and are most probably complexed to transferrin.

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The Blood-Brain Barrier in Infectious Diseases Its Permeability to Toxins in Relation to Their Electrical Charges

Cited by 29 publications

References 17 publications

Polyamine Modification Increases the Permeability of Proteins at the Blood‐Nerve and Blood‐Brain Barriers

Polyamine Modification Increases the Permeability of Proteins at the Blood‐Nerve and Blood‐Brain Barriers

Some peripheral actions of diphtheria toxin

Charge dependence of the distribution of contrast agents in rat cerebral ventricles

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