Gregory F. Oxenkrug

INTENSIFICATION OF THE CENTRAL SEROTONINERGIC PROCESSES AS A POSSIBLE DETERMINANT OF THE THYMOLEPTIC EFFECT

Abstract Psychic depression may result from deficiency of brain serotonin. It is suggested that in depression the production of tryptophane pyrrolase by the liver is stimulated by raised blood-corticosteroid levels. As a result the metabolism of tryptophane is shunted away from serotonin production, and towards kynurenine production. Blood-corticosteroid levels are raised in depression as a consequence of excitement of the amygdaloid complex, on which serotonin is normally an inhibitory influence. Thus, whatever the order of events, a vicious circle is set up. It is suggested that the actions of the various antidepressant treatments in use have a common mechanism—namely, the intensification of the central serotoninergic processes. The thymoleptic action of imipramine-like tricyclic antidepressants results from potentiation of serotoninergic effects on the brain; these effects include inhibition of the amygdala, which suppresses central mechanisms of stress normally manifested in anxiety, tension, and fear. The mood-elevating component of the antidepressant actions of monoamine-oxidase inhibitors and of electroconvulsive therapy is related to the increase in brain serotonin levels. Activation of central adrenergic mechanisms is responsible for psychoenergetic and motor-stimulating effects of antidepressants, but not for their mood-elevating actions.

Mitochondria as a Target for Neurotoxins and Neuroprotective Agents

Abstract: Mitochondrial permeability transition pores represent a multiprotein complex that includes components of both inner and outer membrane. The pores regulate transport of ions and peptides in and out of mitochondria, and their regulation is associated with a general mechanism for maintaining Ca2+ homeostasis in the cell and apoptosis. Various pathologic factors may induce a pathologic activation of the permeability transition and an irreversible opening of mitochondria pores. This event is a major step in the development of neurotoxicity and neurodegeneration. This paper explores the effect of MPP+ and β‐amyloid fragment 25‐35, neurotoxins that are known to generate Parkinsons‐like syndrome and Alzheimers disease, on the regulation of the mitochondrial pores. Both neurotoxins induce opening of mitochondrial pores, which is prevented by cyclosporin A, a specific inhibitor of the permeability transition. The effect of MPP+ and β‐amyloid may be also prevented by an endogenous precursor of melatonin, N‐acetylserotonin, by an anti‐Alzheimers medication tacrine, and by dimebon, which is in development as an agent for the therapy of Alzheimers disease and other types of dementia. The paper illustrates that the effect on mitochondrial pores is an important aspect of the mechanism of neurotoxicity. Substances that may prevent opening of mitochondrial pores induced by neurotoxins may preserve the mitochondrial function and, thus, may have potential as neuroprotective agents.

Aging and cortisol resistance to suppression by dexamethasone: a positive correlation

Cortisol resistance to suppression by 0.5 mg of dexamethasone given at 11 p.m. was studied in 30 normal subjects, 17 to 78 years of age. Serum cortisol concentrations were determined by radioimmunoassay. A strong positive correlation was found between age and cortisol concentrations 9 hours after dexamethasone administration. The data suggest that aging, per se, might contribute to the increased cortisol resistance to suppression by dexamethasone reported in depression and dementia.

Metabolic syndrome, age‐associated neuroendocrine disorders, and dysregulation of tryptophan—kynurenine metabolism

The neuroendocrine theory of aging identified a cluster of conditions (hypertension, obesity, dyslipidemia, diabetes type 2, menopause, late onset depression, vascular cognitive impairment, impairment of immune defense, and some forms of cancer, e.g., breast and prostate) as age‐associated neuroendocrine disorders (AAND). Obesity, dyslipidemia, hypertension, and type 2 diabetes were later described as metabolic syndromes (MetS). Chronic inflammation is currently considered as a common feature of MetS/AAND. One of the mechanisms by which chronic inflammation might trigger and/or maintain the development of MetS/AAND is transcriptional induction of indoleamine 2,3‐dioxygenase (IDO), rate‐limiting enzyme of tryptophan (TRY)–kynurenine (KYN) pathway, by pro‐inflammatory cytokines (PIC). Activation of IDO shifts TRY metabolism from serotonin synthesis to formation of “kynurenines.” Diminished serotonin production is associated with mental depression while increased formation of kynurenines might contribute to development of MetS/AAND via their apoptotic, neurotoxic, and pro‐oxidative effects, and upregulation of inducible nitric oxide synthase, phospholipase A2, arachidonic acid, prostaglandin, 5‐lipoxygenase, and leukotriene cascade. The combined presence of high producers of alleles of polymorphic PIC genes (e.g., interferon‐gamma and tumor necrosis factor alpha) might account for the genetic predisposition to high levels of PIC production, leading to “superinduction” of IDO. The other rate‐limiting enzyme of the TRY–KYN pathway, TRY 2,3‐dioxygenase, is activated by substrate (TRY) and cortisol. Therefore, KYN–TRY metabolism might be the meeting point for gene‐environment interaction and a new target for prevention and treatment of MetS/AAND.

Anticonvulsant activity of melatonin against seizures induced by quinolinate, kainate, glutamate, NMDA, and pentylenetetrazole in mice

Abstract: Melatonin was tested in an ongoing attempt to find the endogenous antagonists of quinolinic acid, an endogenous convulsant. Among a great number of metabolites that have been tried before, only a few were found (cerulein and quinaldic acid in mice and kynurenic acid in rats). In SHR (bred from Swiss) male mice, intracerebroventricular (i.c.v.) pretreatment with melatonin (1.25–10.0 μg) attenuated (in the descending order of potency) the convulsant effect of i.c.v. administered kainate, quinolinate, glutamate, N‐methyl‐D‐aspartate, and pentylenetetrazole. Melatonin was ineffective against i.p. administered pentylenetetrazole. Systemically (intraperitoneal, i.p.) administered melatonin (12.5–100.0 mg/kg) attenuated the convulsant effect of quinolinate, while the action of other convulsants used remained unaltered. It is suggested that melatonin could be tried against grand ma1 seizures in epileptic patients.

Genetic and hormonal regulation of tryptophan kynurenine metabolism: implications for vascular cognitive impairment, major depressive disorder, and aging.

Impairment of cognition that is caused by (or associated with) vascular factors has been termed vascular cognitiveimpairment (VCI). The hallmark of VCI is an impairment of brain executive, or planning, functions caused by inflammatory changes of brain microvessels. VCI is characterized by impairment of the executive function and is distinct from Alzheimers‐type and multi‐infarct dementias, although VCI might overlap with Alzheimers disease. This review focuses on the possible contribution of the kynurenine pathway of tryptophan (Try) catabolism to the inflammatory changes in brain microvessels. One mechanism of brain microvessel inflammation is activation of the inducible nitric oxide synthase (iNOS) by the proinflammatory cytokine interferon gamma (IFN‐γ). The effect of IFN‐γ on iNOS might be mediated by kynurenine derivatives of tryptophan because (1) IFN‐γ stimulates the rate‐determining enzyme of the Try–kynurenine pathway, indoleamine‐2,3‐dioxygenase (IDO) and (2) some kynurenines (e.g., quinolinic and picolinic acids) can stimulate iNOS. IFN‐γ production is controlled by (IFN‐γ) + 874(T/A) genotypes, suggesting the association of a high promoter T allele with the high rate of IFN‐γ production and, consequently, with activated IDO and enhanced production of kynurenines. Although IDO is strictly an IFN‐γ–induced gene product, tumor necrosis factor α (TNF‐α) can synergistically increase the transcriptional activation of the IDO gene in response to IFN‐γ. The combination of high promoter T of (IFN‐γ) + 874(T/A) with high promoter A of (TNF‐α) – 308(G/A) might “superinduce” IDO and cause (or contribute to) inflammation of brain microvessels detected as white matter hyperintensities and leading to VCI development. Hormonal induction of tryptophan dioxygenase and the ability of hormones to potentiate IFN‐γ–induced activation of IDO might contribute to the development of inflammatory changes in major depressive disorder and in aging. The IFN‐γ–IDO–iNOS hypothesis of VCI suggests new ways of preventing (identifying population at risk by analysis of IFN‐γ and TNF‐α genetic polymorphism) and treating VCI (using IDO inhibitors and melatonin and bupropion [Wellbutrin] as agents suppressing IFN‐γ and TNF‐α production).

Effects of Pinealectomy and Aging on the Serum Corticosterone Circadian Rhythm in Rats

Male Sprague‐Dawley rats were housed in alternate light/dark conditions (light on, 7:00 AM, light off, 7:00 PM). Corticosterone was determined by radioimmunoassay from blood samples that were obtained by tail clip at 4‐h intervals. Pinealectomized animals have shown significant increase of corticosterone levels at 7:00 AM, 11:00 AM and 7:00 PM in comparison with 2‐month‐old intact rats. There were no differences in serum corticosterone rhythm between 24‐month‐old and pinealectomized animals. Twelve‐month‐old rats have shown significant increase of corticosterone levels at 7:00 and 11:00 AM in comparison with 2‐month‐old animals.

Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated psychiatric and medical disorders.

This review of literature and our data suggests that up-regulated production of interferon-gamma (IFNG) in periphery and brain triggers a merger of tryptophan (TRY)–kynurenine (KYN) and guanine–tetrahydrobiopterin (BH4) metabolic pathways into inflammation cascade involved in aging and aging-associated medical and psychiatric disorders (AAMPD) (metabolic syndrome, depression, vascular cognitive impairment). IFNG-inducible KYN/pteridines inflammation cascade is characterized by up-regulation of nitric oxide synthase (NOS) activity (induced by KYN) and decreased formation of NOS cofactor, BH4, that results in uncoupling of NOS that shifting arginine from NO to superoxide anion production. Superoxide anion and free radicals among KYN derivatives trigger phospholipase A2-arachidonic acid cascade associated with AAMPD. IFNG-induced up-regulation of indoleamine 2,3-dioxygenase (IDO), rate-limiting enzyme of TRY–KYN pathway, decreases TRY conversion into serotonin (substrate of antidepressant effect) and increases production of KYN associated with diabetes [xanthurenic acid (XA)], anxiety (KYN), psychoses and cognitive impairment (kynurenic acid). IFNG-inducible KYN/pteridines inflammation cascade is impacted by IFNG (+874) T/A genotypes, encoding cytokine production. In addition to literature data on KYN/TRY ratio (IDO activity index), we observe neopterin levels (index of activity of rate-limiting enzyme of guanine–BH4 pathway) to be higher in carriers of high (T) than of low (A) producers alleles; and to correlate with AAMPD markers (e.g., insulin resistance, body mass index, mortality risk), and with IFN-alpha-induced depression in hepatitis C patients. IFNG-inducible cascade is influenced by environmental factors (e.g., vitamin B6 deficiency increases XA formation) and by pharmacological agents; and might offer new approaches for anti-aging and anti-AAMPD interventions.

Stress causes an increase in endogenous monoamine oxidase inhibitor (tribulin) in rat brain

Two hours of cold restraint stress in rats resulted in significantly increased brain concentrations of endogenous monoamine oxidase inhibitor (tribulin). Young and old rats showed the same order of response. Tribulin levels were also increased by immobilisation stress alone but to a lesser extent.

Insulin Resistance and Dysregulation of Tryptophan–Kynurenine and Kynurenine–Nicotinamide Adenine Dinucleotide Metabolic Pathways

Insulin resistance (IR) underlines aging and aging-associated medical (diabetes, obesity, dyslipidemia, hypertension) and psychiatric (depression, cognitive decline) disorders. Molecular mechanisms of IR in genetically or metabolically predisposed individuals remain uncertain. Current review of the literature and our data presents the evidences that dysregulation of tryptophan (TRP)–kynurenine (KYN) and KYN–nicotinamide adenine dinucleotide (NAD) metabolic pathways is one of the mechanisms of IR. The first and rate-limiting step of TRP–KYN pathway is regulated by enzymes inducible by pro-inflammatory factors and/or stress hormones. The key enzymes of KYN–NAD pathway require pyridoxal-5-phosphate (P5P), an active form of vitamin B6, as a cofactor. Deficiency of P5P diverts KYN–NAD metabolism from production of NAD to the excessive formation of xanthurenic acid (XA). Human and experimental studies suggested that XA and some other KYN metabolites might impair production, release, and biological activity of insulin. We propose that one of the mechanisms of IR is inflammation- and/or stress-induced upregulation of TRP–KYN metabolism in combination with P5P deficiency-induced diversion of KYN–NAD metabolism towards formation of XA and other KYN derivatives affecting insulin activity. Monitoring of KYN/P5P status and formation of XA might help to identify subjects at risk for IR. Pharmacological regulation of the TRP–KYN and KYN–NAD pathways and maintaining of adequate vitamin B6 status might contribute to prevention and treatment of IR in conditions associated with inflammation/stress-induced excessive production of KYN and deficiency of vitamin B6, e.g., type 2 diabetes, obesity, cardiovascular diseases, aging, menopause, pregnancy, and hepatitis C virus infection.