Biologically based treatment approaches to the patient with resistant perinatal depression
ARCHIVES OF WOMENS MENTAL HEALTH
2013; 16 (5): 343-351
An Internal Signal Sequence Directs Intramembrane Proteolysis of a Cellular Immunoglobulin Domain Protein
JOURNAL OF BIOLOGICAL CHEMISTRY
2008; 283 (52): 36369-36376
This study aims to summarize the current state of knowledge regarding approaches to treatment-resistant depression in pregnancy and the postpartum period and to develop algorithms for ante- and postnatal management in cases of refractory major depression. PubMed, Scopus, Google Scholar, and the Cochrane Library databases were searched without temporal restriction. Search terms included pregnancy and depression, perinatal depression, postnatal depression, treatment resistance and depression, antipsychotics and pregnancy, antidepressants and pregnancy, and mood stabilizers and pregnancy. Abstracts were reviewed for relevance, and further articles were obtained from bibliographic citations. There is a significant subpopulation of patients in pregnancy and postpartum whose depressive symptoms do not respond to first-line treatments. No research studies have focused specifically on this population. Data extracted from studies on women with depressive symptoms in pregnancy suggest that in the absence of evidence on which to base clinical decisions, many are receiving combinations of psychotherapeutic medications that have not been specifically studied for use in pregnancy. Antidepressant use in pregnancy is well studied, but studies specifically addressing the case of the patient who does not respond to first-line treatments are absent. Research in this area is urgently needed. The authors review a number of possible therapeutic approaches to treatment-resistant depression in pregnancy and the postpartum period.
View details for DOI 10.1007/s00737-013-0366-7
View details for Web of Science ID 000324337700001
View details for PubMedID 23828097
Literature review, case report, and expert discussion of prolonged refractory status epilepticus
2006; 4 (1): 35-46
Precursor proteolysis is a crucial mechanism for regulating protein structure and function. Signal peptidase (SP) is an enzyme with a well defined role in cleaving N-terminal signal sequences but no demonstrated function in the proteolysis of cellular precursor proteins. We provide evidence that SP mediates intraprotein cleavage of IgSF1, a large cellular Ig domain protein that is processed into two separate Ig domain proteins. In addition, our results suggest the involvement of signal peptide peptidase (SPP), an intramembrane protease, which acts on substrates that have been previously cleaved by SP. We show that IgSF1 is processed through sequential proteolysis by SP and SPP. Cleavage is directed by an internal signal sequence and generates two separate Ig domain proteins from a polytopic precursor. Our findings suggest that SP and SPP function are not restricted to N-terminal signal sequence cleavage but also contribute to the processing of cellular transmembrane proteins.
View details for DOI 10.1074/jbc.M807527200
View details for Web of Science ID 000261840500034
View details for PubMedID 18981173
Toxicity of glutathione depletion in mesencephalic cultures: a role for arachidonic acid and its lipoxygenase metabolites
EUROPEAN JOURNAL OF NEUROSCIENCE
2004; 19 (2): 280-286
We report the case of a 30-year-old woman with severe, prolonged refractory status epilepticus requiring more than 6 months of iatrogenic coma. Opinions on prognosis and clinical management were solicited from a number of experienced neurointensivists and epileptologists at multiple time-points during the clinical course. The ensuing discussion, annotated with references, is presented here. Several experts commented on isolated cases of young patients with encephalitis requiring up to 2-3 months of iatrogenic coma, yet still having good outcomes. Treatments discussed include ketamine, gammaglobulin, plasmapheresis, steroids, adrenocorticotropic hormone, very high-dose phenobarbital, isoflurane, lidocaine, electroconvulsive therapy, ketogenic diet, hypothermia, magnesium, transcranial magnetic stimulation, vagus nerve stimulation, deep brain stimulation, and neurosurgery. The patient eventually suffered a cardiac arrest but was resuscitated as requested by the family. Seizures then stopped, and the patient has remained in a persistent vegetative state since.
View details for Web of Science ID 000203000400009
View details for PubMedID 16498194
Lipopolysaccharide prevents cell death caused by glutathione depletion: Possible mechanisms of protection
2002; 114 (2): 361-372
The contribution of arachidonic acid (AA) release and metabolism to the toxicity that results from glutathione (GSH) depletion was studied in rat mesencephalic cultures treated with the GSH synthesis inhibitor l-buthionine sulfoximine. Our data show that GSH depletion is accompanied by increased release of AA, which is phosholipase A2 (PLA2) dependent. Exogenous AA is toxic to GSH-depleted cells. This toxicity is prevented by inhibition of lipoxygenase activity, suggesting participation of toxic byproducts of AA metabolism. Hydroxyperoxyeicosatetraenoic acid (HPETE), one of the primary products of AA metabolism by lipoxygenase is also toxic to GSH-depleted cells, whereas hydroeicosatetraenoic acid (HETE) is not. Cell death caused by GSH depletion is prevented by: (i) replenishment of GSH levels with GSH-ethyl ester; (ii) inhibition of PLA2 activity; (iii) inhibition of lipoxygenase activity; and (iv), treatment with ascorbic acid. These data suggest that the following events likely contribute to cell death when GSH levels become depleted. Loss of GSH results in increased release of AA, which is PLA2 dependent. Metabolism of arachidonic acid via the lipoxygenase pathway results in generation of oxygen free radicals possibly produced during conversion of HPETE to HETE, which contribute to cellular damage and death. Our study suggests that limiting AA release and metabolism may provide benefit in conditions with an existing depletion of GSH, such as Parkinson's disease.
View details for DOI 10.1046/j.1460-9568.2003.03111.x
View details for Web of Science ID 000188224800007
View details for PubMedID 14725622
Glutathione is an important cellular antioxidant present at high concentrations in the brain. We have previously demonstrated that depletion of glutathione in mesencephalic cultures results in cell death and that the presence of glia is necessary for the expression of toxicity. Cell death following glutathione depletion can be prevented by inhibition of lipoxygenase activity, implicating arachidonic acid metabolism in the toxic events. In this study we examined the effect of glial activation, known to cause secretion of cytokines and release of arachidonic acid, on the toxicity induced by glutathione depletion. Our data show that treatment with the endotoxin lipopolysaccharide activated glial cells in mesencephalic cultures, increased interleukin-1beta in microglia and caused depletion of glutathione. The overall effect of lipopolysaccharide treatment, however, was protection from damage caused by glutathione depletion. Addition of cytokines or growth factors, normally secreted by activated glia, did not modify L-buthionine sulfoximine toxicity, although basic fibroblast growth factor provided some protection. A large increase in the protein content and the activity of Mn-superoxide dismutase, observed after lipopolysaccharide treatment, may indicate a role for this mitochondrial antioxidant enzyme in the protective effect of lipopolysaccharide. This was supported by the suppression of toxicity by exogenous superoxide dismutase. Our data suggest that superoxide contributes to the damage caused by glutathione depletion and that up-regulation of superoxide dismutase may offer protection in neurodegenerative diseases associated with glutathione depletion and oxidative stress.
View details for Web of Science ID 000178316200010
View details for PubMedID 12204205