Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence.

Emerging preclinical and clinical evidence suggests that pregnenolone may be a promising novel therapeutic candidate in schizophrenia. Pregnenolone is a neurosteroid with pleiotropic actions in rodents that include the enhancement of learning and memory, neuritic outgrowth, and myelination. Further, pregnenolone administration results in elevations in downstream neurosteroids such as allopregnanolone, a molecule with neuroprotective effects that also increases neurogenesis, decreases apoptosis and inflammation, modulates the hypothalamic-pituitary-adrenal axis, and markedly increases GABA(A) receptor responses. In addition, pregnenolone administration elevates pregnenolone sulfate, a neurosteroid that positively modulates NMDA receptors. There are thus multiple mechanistic possibilities for pregnenolone as a potential therapeutic agent in schizophrenia, including the amelioration of NMDA receptor hypofunction (via metabolism to pregnenolone sulfate) and the mitigation of GABA dysregulation (via metabolism to allopregnanolone). Additional evidence consistent with a therapeutic role for pregnenolone in schizophrenia includes neurosteroid changes following administration of certain antipsychotics in rodent models. For example, clozapine elevates pregnenolone levels in rat hippocampus, and these increases may potentially contribute to its superior antipsychotic efficacy [Marx et al. (2006a) Pharmacol Biochem Behav 84:598-608]. Further, pregnenolone levels appear to be altered in postmortem brain tissue from patients with schizophrenia compared to control subjects [Marx et al. (2006c) Neuropsychopharmacology 31:1249-1263], suggesting that neurosteroid changes may play a role in the neurobiology of this disorder and/or its treatment. Although clinical trial data utilizing pregnenolone as a therapeutic agent in schizophrenia are currently limited, initial findings are encouraging. Treatment with adjunctive pregnenolone significantly decreased negative symptoms in patients with schizophrenia or schizoaffective disorder in a pilot proof-of-concept randomized controlled trial, and elevations in pregnenolone and allopregnanolone post-treatment with this intervention were correlated with cognitive improvements [Marx et al. (2009) Neuropsychopharmacology 34:1885-1903]. Another pilot randomized controlled trial recently presented at a scientific meeting demonstrated significant improvements in negative symptoms, verbal memory, and attention following treatment with adjunctive pregnenolone, in addition to enduring effects in a small subset of patients receiving pregnenolone longer-term [Savitz (2010) Society of Biological Psychiatry Annual Meeting New Orleans, LA]. A third pilot clinical trial reported significantly decreased positive symptoms and extrapyramidal side effects following adjunctive pregnenolone, in addition to increased attention and working memory performance [Ritsner et al. (2010) J Clin Psychiatry 71:1351-1362]. Future efforts in larger cohorts will be required to investigate pregnenolone as a possible therapeutic candidate in schizophrenia, but early efforts are promising and merit further investigation. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

Heat-induced conformational changes of patatin, the major potato tuber protein.

This paper presents a first structural characterization of isolated patatin, the major potato tuber protein, at ambient and elevated temperatures. Isolated patatin at room temperature is a highly structured molecule at both secondary and tertiary levels. It is estimated from far-ultraviolet circular dichroism data that about 33% of the residues adopts an alpha-helical and 46% a beta-stranded structure. Patatin is thermally destabilized at temperatures exceeding 28 degrees C, as was indicated by near-ultraviolet circular dichroism. It was shown that parts of the alpha-helical contributions unfold in the 45-55 degrees C region, whereas the beta-stranded parts unfold more gradually at temperatures of 50-90 degrees C. This was confirmed with Fourier-transform infrared spectroscopy. Differential scanning calorimetry indicated a cooperative transition between 50-60 degrees C, most likely reflecting the unfolding of alpha-helical parts of the molecule. Furthermore, fluorescence spectroscopy confirmed a global unfolding of the protein between 45-55 degrees C. The observed unfolding of the protein coincides with the inactivation of the patatin enzyme activity and with the precipitation as occurs in the potato fruit juice upon heating. At high temperatures, patatin still contains some helical and stranded structures. Upon cooling the protein partly refolds, it was observed that mainly alpha-helical structures were formed.

Respiratory sinus arrhythmia versus neck/trapezius EMG and incentive inspirometry biofeedback for asthma: a pilot study.

This pilot study compared biofeedback to increase respiratory sinus arrhythmia (RSA) with EMG and incentive inspirometry biofeedback in asthmatic adults. A three-group design (Waiting List Control n = 5, RSA biofeedback n = 6, and EMG biofeedback n = 6) was used. Six sessions of training were given in each of the biofeedback groups. In each of three testing sessions, five min. of respiratory resistance and EKG were obtained before and after a 20-min biofeedback session. Additional five-min epochs of data were collected at the beginning and end of the biofeedback period (or, in the control group, self-relaxation). Decreases in respiratory impedance occurred only in the RSA biofeedback group. Traub-Hering-Mayer (THM) waves (.03-.12 Hz) in heart period increased significantly in amplitude during RSA biofeedback. Subjects did not report significantly more relaxation during EMG or RSA biofeedback than during the control condition. However, decreases in pulmonary impedance, across groups, were associated with increases in relaxation. The results are consistent with Vaschillo's theory that RSA biofeedback exercises homeostatic autonomic reflex mechanisms through increasing the amplitude of cardiac oscillations. However, deep breathing during RSA biofeedback is a possible alternate explanation.

Selective reminding procedure in depression and dementia.

Patients with mild dementia of the Alzheimer's type (DAT), patients with major depression, and normal elderly control subjects were administered a verbal learning task using the selective reminding procedure. Depressed patients were impaired on total recall and the proportion of items retained from one trial to the next without reminding and did not benefit from imagery in retaining items over consecutive trials. The DAT patients were impaired on all measures derived from the test, including storage and recognition memory. With the exception of the ability to benefit from imagery, all of the measures distinguished depressed and mild DAT patients. These findings are consistent with deficient encoding in DAT and performance deficits as a function of effortful cognitive processing in depression.