Eicosanoids are products of arachidonic acid (AA), an essential fatty acid. They include prostaglandins (PGs), prostacyclin (PGI2), thromboxanes (TXs), leuko-trienes (LTs) and hydroxy fatty acids. AA is derived enzymatically from membrane phospholipids and to a lesser extent the diet. Eicosanoids self-regulate every cell,including those synthesizing serotonin, norepinephrine and dopamine and thos esubserving immune function, such as T-cells, B-cells, natural killer cells, macrophages, monocytes and dendritic cells. There is objective evidence that prostaglandinsregulate the physiology of the hypothalamic –pituitary – adrenal axis (HPA).
Elucidation of the structure and metabolic pathways of eicosanoids galvanizedresearchers into illuminating their role in physiology, pathology and pharmacology.Striking contradictions arose: eicosanoids were shown to activate and suppress microorganisms, potentiate and suppress immunity and possess pro- and anticancer properties. as prostaglandins are the most heavily studied eicosanoids in the contextof mood and immunity I will focus on them in this article. I will present evidence of the immunostimulating and antimicrobial properties of lithium and antidepressants and propose that these properties are linked to the antiprostaglandin actions of these compounds.
(© 2004 The British Infection Society. Published by Elsevier ltd. all rights reserved.)
Eicosanoids, the metabolic products of arachidonicacid, include prostaglandins (PGs), leukotrienes (LTs), prostacyclin (PGI2) thromboxanes (TXs) andlipoxins. Eicosanoids self-regulate every cell including those subserving immune function and those subserving mood. They self-regulate all cells insynapses, in neuro-immune interfaces and in the hypothalamic – pituitary– adrenal axis (HPA).
Bacteria, parasites and fungi synthesize eicosanoids.
Bacteria, parasites, fungi and viruses have the ability to induce eicosanoid synthesis in host cells. The ability of the host to resist such induction in?uences the outcome of exposure. an increase in production ofPGs in the immune system may lead to the activationof a dormant virus. While in vitro studies show that lithium and antidepressants have direct antimicrobial properties their actions on the brain may be responsible for their immunostimulating properties.
PGs are highly active in the brain.[1] Prostaglandin E1 (PGE1) is elevated in the platelets of manics and reduced in those of depressives, while prostaglandin E2 (PGE2) is increased in the platelets of depressives.[2] PGE2 and thromboxane B2 (TXB2) are elevated in the plasma of depressives,[3] PGE2 in their cerebrospinal ?uid [4] and saliva.[5] When administered intravenously to alleviate Raynaud’s syndrome or phenomenon prostacyclin can precipitate acute depression.[6] A prostacyclin analogue caninduce depressive effects in mice.[7]
The literature on the role of eicosanoids inimmune regulation and the physiology of micro-organisms mainly involves PGs. PGs have diverseactions on humoral and cellular immunity, including modulation of natural killer cell activity,[8] delivery of signals leading to T-cell activation,[9] induction of dendritic cells,[10] control of suppressor cell and B-cell activation and modulation of macrophage-T lymphocyte interactions.[11]
The relationship between PGs and viruses has been studied with many viruses,[12] most intensively the human immu-node?ciency virus (HIV). PGE2 creates a selectionpressure favouring HIV at many host/virus inter-faces. where HIV comes into contact with AA itconverts it into PGE2.
Monocytes from drug-addicts with AIDS elaborate elevated concentrations of PGE2.[13] A soluble factor of transformed B-lympho-cytes in patients with HIV infection stimulatesmonocytes to produce PGE2.[14] an HIV glycoproteininduces monocyte AA metabolites [15] and promotesapoptosis in rat brain by deranging the AA cascadein favour of PGs.[16] Secretion of PGE2 by macro-phages induces signalling events resulting in acti-vation of pro-viral DNA in T-cells latently infected with HIV-1.[17] Humans with AIDS dementia have a marked increase in PGE2 in their spinal ?uid;[18] this PG may be responsible for the immuno-suppression that is the hallmark of AIDS.
PGs are present in high concentrations in thesaliva of such blood-sucking arthropods as ticks. PGs are involved in parasite metabolism and physiology. They facilitate feeding by increasing local blood ?ow and prolong attachments of ticks by suppressing immune mechanisms.[19] Release of PGs by protozoa and metazoa play a role in penetration, immune suppression, in?ammation and modulationof haemostasis.[19]
Induction of two-series PGs bysuch parasites as Schistosoma,[20] Leishmania dono-vani, [21] Amoeba, [22] Fasciola, [23] and Trypanasoma [24]suppress immune responses in favour of thepathogen.
Induction of PGs and their synthesizing enzymes are responsible for many of the symptoms of bacterial infection including the immunosuppression.[25 – 31] Pathogenic fungi such as Cryptococcusneoformans and Candida albicans produce and respond to immuno-modulatory PGs.[32 – 35] PGs regulate the physiology, immunity, reproduction and toxicity of microorganisms and the resistance of their hosts. The virulence of a pathogen and the resistance of the host determine how negatively the host will be affected.[36 – 46]
As aspirin inhibits cyclooxygenase (COX), the primary PG synthesizing enzyme, it was inferred that this mechanism accounts for its analgesic, anti-in?ammatory and antipyretic properties. Compounds that inhibit COX were synthesized, inparallel with research showing that PGs causemany in?ammatory, infectious, neoplastic and reproductive disorders. The failure of prostaglandin synthesis inhibitors, also known as non-steroidalanti-in?ammatory drugs (NSAIDs) in infectious disorders led to the conclusion that PG inhibition has limited clinical application in infection.
Isolation of the COX isomer, COX-2, and the synthesis of selective COX-2 inhibitors have stimulated considerable investment by the pharmaceutical industry in such inhibitors. COX-2 inhibitors are claimed to have a reduced risk of gastrointestinal hemorrhage when compared to NSAIDs. all the while the PG inhibiting properties of lithium and anti-depressants have been neglected, along with their unique immunopotentiating and antimicrobialactions.
Lithium carbonate inhibits the synthesis of PGE1,[47 – 50] decreases phospholipase A2 activity [51 – 53] and the turnover of AA in several brain phospholi-pids,[51] and reduces brain concentrations of COX-2 and PGE2. [53] Monoamine oxidase inhibitors (MAOIs) inhibit PGE2 synthesis by limiting the mobilizationof AA. [54 – 56]
Tricyclic antidepressants (TCAs) are weak PG agonists and powerful PG and TX antagonists.[57]
TCAs uniquely and powerfully activate the PG degrading enzyme, 15-hydroxyprostaglandin dehydrogenase. [58] Fluoxetine, a speci?c serotonin reuptake inhibitor (SSRI), inhibits the synthesis of two-series PGs. [59] The MAOI tranylcyprominereduces the levels of prostaglandin D2 in the brainsof mice.[60] given the PG-opposing properties of these agents, reports of their immunopotentiating and antimicrobial actions are not surprising. ThePG-opposing actions of lithium and antidepressants support the role of PGs in mood disorders.
In the early 1950’s clinicians observed that patientstreated for tuberculosis with the MAOIs isoniazid and iproniazid were energized. This observation was the foundation of the pharmacology of depression and became part of its folklore. that MAOIs have dual antimicrobial and antidepressant properties failed to have an impact on the pharmacology of infectious disorders. Remission of such manifestations of viral infections assinusitis, sinobronchitis, frequent colds, sorethroats, cold sores and genital herpes in patientstaking lithium carbonate has been reported.[61 – 65]
In a retrospective study of the antiviral activity of various psychotropic agents, chronic lithium administration reduced the mean rate of recurrent labial herpes infections. Lithium and antidepressants reduced the mean yearly rates of common, ‘?u-like’colds.[63,64] In a randomised, double blind, placebo [64] controlled study lithium reduced the frequency andduration of recurrences of genital herpes.[64]
The polymorphonuclear leukocytes (PMN) of a 29-year-old woman with eczema and recurrent staphylococcal and streptococcal skin infections were unresponsive to standard chemotactic stimuli.
In vitro addition of lithium to her PMN preparations restored their chemotactic response. After receiving lithium carbonate, 1 g per day for 5 weeks she became free of infection and relapsed when lithium was withdrawn.[66]
Lithium chloride prevents replication of type 1 and 2 herpes virus in baby hamster kidney cells. Virus particle production, polypeptide and antigen synthesis were unaffected while viral DNA synthesis was inhibited. The replication of two other DNA viruses, pseudo rabies and vaccinia virus was inhibited but two RNA viruses, EMC and in?uenza virus were not inhibited.[67] Lithium augments several in vitro immune reactions. It increases rosette formation and thymidine incorporation by lymphocytes and phagocytosis by macrophages.[67] It reverses the PGE1 inhibition ofthe lymphocyte response to phytohemag glutinin,and enhances immunoglobulin synthesis by human lymphocytes.[68]
MAOIs can remit tuberculosis, aphthous ulcers,[69,70] cold sores, genital herpes, [71] upper respiratory tractinfections and plantar warts.[72] Furazolidone, the veterinary antibiotic, is a MAOI.[73]
TCAs can remitaphthous ulcers, [74] reduce the frequency of recurrences of herpes zoster, remit the pain of this disorder and prevent post herpetic neuralgia.[75] such TCAs as clomi-pramine and imipramine can destroy in vitro leishmania minor and major, the agents of kalaazar and Old World cutaneous leishmaniasis,[76] and inhibit the growth of the intestinal parasite Giardia lamblia.[77] The TCA’s desipramine, imipramine and amitriptyline have antimalarial properties.[78] Many antidepressants enhance in vitro susceptibility to chloroquine in resistant Plasmodiumfalciparum.[79 – 82] Various antidepressants are lethal in vitro against Trypanasoma parasites.[83]
Selective serotonin reuptake inhibitors (SSRIs)can destroy such fungi in vitro as Candida and Aspergillus species.[84] Sertraline can remit recurrent vulvovaginal candidiasis in vivo.[85] Munoz-Bellido and colleagues have shown that such antidepressants as sertraline, ?uoxetine and paroxetine have antimicrobial activity especially against Gram-positive microorganisms. These anti-depressants also show synergistic activity when combined with some antibiotics against several bacteria.[86] In a separate study Munoz-Bellido andcolleagues tested the in vitro activity of various antibiotics and psychotropic drugs against 32 strains of Corynebacterium urealyticum. Sertraline was the most effective psychiatric drug and it enhanced the activity of cipro?oxacin and tetracycline against all strains.[87]
The depressive effect of bereavement and other stresses on immune function is well documented.[88] Impaired lymphocyte function, reduced natural killer cell activity, reduced lymphocyte responses to mitogens and decreased natural killer cellpopulations have been demonstrated in depressives.[89,90] Antidepressants augment natural killer cell activity in vivo and in vitro.[91] The MAOI tranylcypromine enhances cell-mediated immunity.[92]
PGs play a key role in mediating the HPA axis response to immune insults.[93] PGs are involved innicotine and carbachol-induced [94] ACTH and corti-costerone secretion in control and stressed rats.[95] In rats interleukin-1 beta stimulates PG synthesis inthe HPA axis by acting on receptors located chie?y on endothelial cells.[96] The autonomic nervoussystem innervates lymphoid organs and is an important regulator of immune function in ani-mals.[97,98] every cell in the sympathetic system andin lymphoid organs is self-regulated by PGs. In self-regulating every cell and signalling between them PGs regulate every site at which neurons make contact with the immune system.
While lithium is effective against some bacteria and viruses evidence for effectiveness against parasites and fungi is lacking. Antidepressants, on the other hand, are effective against various bacteria, viruses, parasites and fungi. as lithium and anti-depressants have immunopotentiating as well as antimicrobial properties they stand to be effective against a gamut of microorganisms. The response of infection to lithium and antidepressants mirrors depression with subjects responding to TCAs, to SSRIs, to MAOIs or to lithium. an infection should not be labeled refractory to antidepressants untilmany, if not all have been tried. Many comparison studies with antidepressants are biased by the generalization that ‘antidepressants’ lack a speci?c property when the study involved only one. Anti-depressants are highly speci?c and humans remarkably variable.
Excessive synthesis of PGs depresses brain and immune function. When depressives with an infection respond to lithium or an antidepressant the response is invariably simultaneous, suggesting that the central actions of the drugs are important.
The immunostimulating actions of lithium and anti-depressants are systemic and suggest central orchestration. While antivirals are not necessarily immunostimulants, the actions of lithium and anti-depressants suggest that immunostimulants are antivirals. The SARS epidemic was a clarion call for immunostimulants. The immunostimulating properties of lithium and antidepressants couldtransform the prevention and treatment of many such infections.
Tachyphylaxis may complicate the treatment of depression[99 – 101] and paradoxical reactions induce or intensify symptoms. These phenomena may interfere with the treatment of infection with lithium and antidepressants. Antidepressants are, paradoxically, capable of activating dormant viruses.[102] Remission of depression in subjectstreated for tuberculosis ushered in the pharmaco-logical treatment of depression.
The wheel will turn full circle when lithium and antidepressants areintegrated into the pharmacology and therapeutics of infection.
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