Central GABAergic systems and depressive illness

Clinical depression and other mood disorders are relatively common mental illnesses but therapy for a substantial number of patients is unsatisfactory. For many years clinicians and neuroscientists believed that the evidence pointed toward alterations in brain monoamine function as the underlying cause of depression. This point of view is still valid. Indeed, much of current drug therapy appears to be targeted at central monoamine function. Other results, though, indicate that GABAergic mechanisms also might play a role in depression. Such indications stem from both direct and indirect evidence. Direct evidence has been gathered in the clinic from brain scans or postmortem brain samples, and cerebrospinal fluid (CSF) and serum analysis in depressed patients. Indirect evidence comes from interaction of antidepressant drugs with GABAergic system as assessed by in vivo and in vitro studies in animals. Most of the data from direct and indirect studies are consistent with GABA involvement in depression.     

Tyrosine metabolism for insect cuticle tanning

Insects have become one of the most successful animal groups in diversity and numbers through the development of a multifunctional exoskeleton and skin, which must be shed periodically in order for them to grow and develop into adults. The evolutionary choice of certain structural materials for the assembly and stabilization of a cuticle with remarkable mechanical and chemical properties has allowed insects to invade terrestrial environments and to evolve flight mechanics for dispersion relatively early in geological history. Diphenolic compounds derived from tyrosine play a central role in sclerotization or tanning of the new cuticle. The phenolic amino acid is stored during larval feeding, and it is mobilized for the production of both structural proteins and diphenolic tanning precursors that are transported into the cuticle. The latter compounds permeate the cuticle and serve as precursors for quinonoid derivatives that both sclerotize and pigment the exoskeleton. This report focuses on how tyrosine and derived diphenolic structures are stored as inactive molecules in preecdysial stages, and how they are released and metabolized to tanning chemicals that stabilize the new cuticle.     

Tyrosine and methionine metabolism in various states of melaninogenesis

Excretion with urine of tyrosine and methionine metabolites as well as the activities of enzymes involved in their metabolism are correlated with the state and type of melanin synthesized in the skin. The response of tyrosine aminotransferase to melaninogenesis induction was more pronounced in animals with predominant pheomelaninogenesis, especially after tyrosine load, while that to dopachrome oxidoreductase--in animals with predominant eumelaninogenesis and after methionine load. Glutathione reductase and cystathionine-beta-synthase responded more vigorously to methionine injections, which was especially well pronounced in animals with prominent pheomelaninogenesis and in albino animals. The metabolic "block" in melanine synthesis in albino animals seems to be observed after the 5-S-cysteinyl-DOPA synthesis, whereas the initial steps of melaninogenesis in these animals are identical to pheomelanine synthesis reactions.     

Altered hippocampal morphology in unmedicated patients with major depressive illness

Despite converging evidence that major depressive illness is associated with both memory impairment and hippocampal pathology, findings vary widely across studies and it is not known whether these changes are regionally specific. In the present study we acquired brain MRIs (magnetic resonance images) from 31 unmedicated patients with MDD (major depressive disorder; mean age 39.2±11.9 years; 77% female) and 31 demographically comparable controls. Three-dimensional parametric mesh models were created to examine localized alterations of hippocampal morphology. Although global volumes did not differ between groups, statistical mapping results revealed that in MDD patients, more severe depressive symptoms were associated with greater left hippocampal atrophy, particularly in CA1 (cornu ammonis 1) subfields and the subiculum. However, previous treatment with atypical antipsychotics was associated with a trend towards larger left hippocampal volume. Our findings suggest effects of illness severity on hippocampal size, as well as a possible effect of past history of atypical antipsychotic treatment, which may reflect prolonged neuroprotective effects. This possibility awaits confirmation in longitudinal studies.     

Tyrosine metabolism in carbidopa and phenylthiourea administered Corcyra cephalonica

The effects of carbidopa and phenylthiourea on dopa decarboxylase and phenoloxidase in relation to their involvement in sclerotization were assessed after injection of these compounds to late last instar Corcyra cephalonica larvae. Carbidopa, on administration, inhibited dopa decarboxylase activity but served as a substrate of phenoloxidase, leading to the development of yellow coloured pupal cuticle. The larvae, injected with phenylthiourea, had reduced phenoloxidase activity, and a prolonged larval period. The control mechanisms of tanning in these insects have been discussed with reference to tyrosine metabolism.     

Mechanisms influencing bone metabolism in chronic illness

Bone is permanently renewed by the coordinated actions of bone-resorbing osteoclasts and bone-forming osteoblasts, which model and remodel bone structure during growth and adult life. The origin of osteoblastic cells (osteoblasts, osteocytes and bone-lining cells) differs from that of osteoclasts, but both cell groups communicate with each other using cytokines and cell-cell contact as to optimally maintain bone homeostasis. This communication in many ways uses the same players as the communication between cells in the immune system. During acute life-threatening illness massive bone resorption is the rule, while bone formation is suppressed. During chronic illness, the balance between bone formation and bone resorption also shifts, frequently resulting in decreased bone mass and density. Several factors may contribute to the osteopenia that accompanies chronic illness, the most important being undernutrition and low body weight, inflammatory cytokines, disorders of the neuroendocrine axis (growth hormone/IGF-1 disturbances, thyroid and gonadal deficiency), immobilization, and the long-term use of glucocorticoids. Their combined effects not only influence the generation and activity of all bone cells involved, but probably also regulate their life span by apoptotic mechanisms. Osteopenia or even osteoporosis and bone fragility, and before puberty also decreased linear growth and lower peak bone mass are therefore frequent consequences of chronic illnesses.     

Evaluation of studies on platelet alpha 2 adrenoreceptors in depressive illness

Discrepant results have been reported from at least ten laboratories regarding the status of platelet alpha 2 adrenoreceptors in depressed patients. Using a statistical test to combine those studies which utilized radioligand binding techniques, we find the overall data support an elevation in density of platelet alpha 2 adrenoreceptors from drug-free depressed patients (p less than 0.05) and suggest a normalization to lower binding values following antidepressant drug treatment (0.05 less than p less than 0.10). However, these positive results are attributable to highly significant findings by only three laboratories. Much of the discrepancy may be attributable to numerous methodological variables which distinguish the studies. Foremost amongst these variables are the use of different platelet size populations, the use of different medium, and the choice of radioactive ligand and competitor (non-radioactive ligand) in the assay. We present a rationale for the proper choice of each methodological condition used in the clinical assessment of platelet alpha 2 adrenoreceptor status, hoping that improved experimental designs will resolve the current controversy.     

Tyrosine phosphatases as regulators of skeletal development and metabolism

The protein tyrosine kinases (PTK) and the protein tyrosine phosphatases (PTPs) are enzymes which play an integral role in tyrosine phosphorylation-dependent signaling cascades. By catalyzing the phosphorylation and dephosphorylation of cellular proteins, these enzymes direct the steady-state levels of specific phosphoproteins and ultimately dictate the functional state of all cells. The importance of this type of signaling in the skeleton is accepted but poorly understood. The contribution of the PTKs to signaling events in bone has been well studied but, in contrast, the regulation by PTPs is poorly defined. The recent identification of 107 genes within the human genome which encode members of the PTP superfamily emphasizes the need to consider the importance of these proteins in skeletal tissue. In this prospective, we will summarize the present state of our knowledge regarding the function of this enzyme superfamily, illustrating its relevance to the development and maintenance of the skeleton and highlighting future directions that should improve our understanding of these critical signaling molecules.     

Electroconvulsive therapy: results in depressive illness from the Leicestershire trial.

Electroconvulsive therapy was investigated in a double blind trial. Altogether 186 clinically selected patients were referred to the trial, but 48 of these did not participate. According to the present state examination, 95 of the remaining 138 patients fell into one of the classes of major depression. Patients were randomly allocated to a course of real or simulated electroconvulsive therapy. Treatment was given twice a week with a maximum of eight treatments. On the Hamilton depressive rating scale the improvement in the group given real treatment was significantly greater than that in the group given simulated treatment both at two weeks (p = 0.014) and at four weeks (p = 0.0001). At follow up at 12 and 28 weeks there was no difference between the treatment groups. At the end of the four week trial consultants, who were blind to the allocation of treatment, rated the patients who had received real treatment as having made a significantly greater improvement than the patients who had received simulated treatment (p less than 0.00005). Further analysis showed that electroconvulsive therapy was effective in depression associated with delusions and in depression associated with retardation.     

Rapid clinical effectiveness of MIF-I in the treatment of major depressive illness

A double-blind 28 day study was conducted to compare the anti-depressant efficacy of MIF-I with that of imipramine. Twenty patients hospitalized with major depressive illness participated. Clinical responses were measured by using the Hamilton Depression Rating Scale, the Global Severity of Illness Scale, the Zung Self-Rating Depression Scale as well as the 100 mm line self-rating for depression. The results indicate that MIF-I was at least as effective as imipramine in this study, and that its anti-depressive effect was a rapid and often dramatic one.