Jacob Peedicayil

A STUDY OF SERUM PROLACTIN LEVELS IN SCHIZOPHRENIA: COMPARISON OF MALES AND FEMALES

1. Serum prolactin levels were measured in large cohorts of schizophrenic patients (67 males and 42 females) and normal subjects (78 males and 42 females).

Epigenetic management of major psychosis

Epigenetic mechanisms are thought to play a major role in the pathogenesis of the major psychoses (schizophrenia and bipolar disorder), and they may be the link between the environment and the genome in the pathogenesis of these disorders. This paper discusses the role of epigenetics in the management of major psychosis: (1) the role of epigenetic drugs in treating these disorders. At present, there are three categories of epigenetic drugs that are being actively investigated for their ability to treat psychosis: drugs inhibiting histone deacetylation; drugs decreasing DNA methylation; and drugs targeting microRNAs; and (2) the role of epigenetic mechanisms in electroconvulsive therapy in these disorders.

The Effect of Organophosphorus Compounds on Serum Pseudocholinesterase Levels in a Group of Industrial Workers

This paper presents the findings of a study of serum pseudocholinesterase activity in a group of 36 industrial workers chronically exposed to organophosphorus (OP) compounds. The mean pseudocholinesterase level of the workers was significantly lower than that of 36 other workers without a history of similar exposure. Although there was a high incidence of clinical features suggestive of OP compound toxicity in the exposed workers, no significant correlation between serum pseudocholinesterase levels and clinical symptoms and signs was found. Six exposed workers, found to have low serum pseudocholinesterase levels, were transferred for 6 months to work areas which did not involve OP exposure, whereupon their levels rose significantly back to the normal range.

Serum-prolactin levels in manic patients

According to the monoamine hypothesis of affective disorders, mania is due to an excess of monoaminergic neurotransmission in the brain (Schildkraut 1969; Ashcroft et al 1972). Although noradrenaline and serotonin have been the monoamines most implicated in the pathophysiology of mania, there is evidence indicating that mania is due to dopaminergic overactMty (Gerner et al 1976; Post et al 1980; Cookson et al 1981; Silverstone 1984; Silverstone and Romans-Clarkson 1989). If there is overactivity of cerebral dopaminergic neurotransmission in mania involving the tuberoinfundibular dopaminergic tract, one could expect serum prolactin levels in manic patients to be less than normal because of the inhibitory effect of dopamine on the release of prolactin from the pituitary. When compared to schizophrenia, very few studies have been conducted on serum prolactin levels in manic patients. The few studies that have been conducted used small numbers of patients and obtained conflicting results (Maeda et al 1979; Cookson et a~ i982; Cookson et al 1983; Hitzemann et ~d 1984; Whalley et al 1985). This study was conducted to detenrfine serum prolactin levels in a cohort of 121 manic patients to see if the levels are influenced by factors such as age, sex, type of clinical presentation, and duration of illness.

Time for clinical trials of epigenetic drugs in psychiatric disorders

We read with great interest the Editorial by van Gerven and Cohen [1], in which they discussed the issue of the dearth of new drugs in clinical psychopharmacology despite the fact that the currently used drugs are often not effective and based on mechanisms that were largely already known in the 1970s. These mechanisms almost exclusively involve the primary neurotransmitters and their receptors. As stated by the authors, however, psychiatric disorders are complex, and cannot be explained adequately only in terms of changes in neurotransmission. In this context, we wish to discuss the relevance of epigenetic therapy in clinical psychopharmacology. Epigenetic therapy, a new development in pharmacology, refers to the correction of epigenetic defects [2, 3]. Such defects involve changes in gene expression without changes in DNA sequence [2, 3]. They include abnormalities in patterns of DNA methylation, histone modifications and abnormalities in RNA-mediated regulation of gene expression [4]. Although there are several classes of epigenetic drugs under investigation, at present most attention is being paid to two drug classes: DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors [2, 3]. There is increasing evidence that epigenetic defects play a major role in the pathogenesis of psychiatric disorders, with some epigenetically modified genes having been implicated in the pathogenesis of these disorders [4, 5]. Interestingly, some of the genes found to be epigenetically modified in patients with psychiatric disorders code for enzymes [6] and receptors [7] involved in the activity of the primary neurotransmitters. There is evidence suggesting that epigenetic drugs may be useful in treating psychiatric disorders. Thus, several psychotropic drugs currently in clinical use have been shown to exhibit epigenetic effects in addition to their commonly understood mechanisms of action [3]; however, epigenetic effects are not the main actions of these drugs. An example of such a drug is the mood stabilizer valproate, which in addition to its well-known actions on nerve conduction, also inhibits HDAC [2, 3]. Epigenetic drugs have also been found to be effective in preclinical trials in the treatment of psychiatric disorders. For example, Tremolizzo et al. [8] showed in a methionine-induced epigenetic mouse model of schizophrenia that valproate enhanced acetylated histone 3 content, prevented methionine-induced hypermethylation of the promoter of the RELN gene, the gene that encodes the protein reelin, and corrected behavioural abnormalities in the mice. Kundakovic et al. [9] found, using cultured NT-2 neuronal precursor cells, that the DNMT inhibitors doxorubicin, azacytidine and zebularine inhibited DNMT1, leading to the activation of the expression of the RELN and glutamic acid decarboxylase 1 (GAD1) genes, both of which have been found to be epigenetically modified in postmortem brains of patients with schizophrenia and bipolar disorder [4]. To our knowledge, except for valproate, no epigenetic drug has undergone clinical trials in patients with psychiatric disorders. As the use of epigenetic drugs in patients with psychiatric disorders appears to be promising, we suggest that it is time for clinical trials of epigenetic drugs in these disorders. Epigenetic therapy may fulfil the need for newer and more effective drugs in clinical psychopharmacology.

Future strategies in psychiatric genetics.

There is evidence suggesting that the primary (idiopathic) mental disorders are due to epimutations involving genes that determine the structure of the brain. Although in the past it has been suggested that the genes underlying the primary mental disorders may be unidentifiable, recent developments in neuroscience suggest otherwise. This paper outlines various epigenetic strategies that may help identify the genes underlying these disorders.

Epigenetic drugs for Alzheimer's disease.

I enjoyed reading the article by Salomone et al. [1] in which they reviewed new pharmacological strategies for treating Alzheimers disease, the most common age-related dementia, focusing on disease modifying drugs. I wish to discuss the role of a group of drugs which were not mentioned by the authors, epigenetic drugs, in treating this disease. Epigenetics, the study of heritable changes in gene expression not involving changes in DNA sequence, involves molecular mechanisms like DNA methylation and modifications of histones (DNA packaging proteins). Epigenetics and the ageing process are known to be intimately linked with each other, and epigenetic patterns in an individual are known to change during the individuals lifetime [2]. Epigenetics is also known to play a major role in cognitive processes including learning and memory [3], and is increasingly known to play a role in the pathogenesis of Alzheimers disease [4]. In fact, epigenetic changes in gene expression are thought to underlie the main pathological feature of Alzheimers disease, amyloid plaques [5]. Histone acetylation, a well studied epigenetic mechanism, is thought to play a critical role in cognitive abilities like learning and memory, and many learning and memory disorders are associated with impaired histone acetylation [3]. Preclinical studies have suggested that epigenetic drugs that increase histone acetylation by inhibiting histone deacetylase (HDAC inhibitors) could be useful in the treatment of Alzheimers disease [6, 7]. Another well studied epigenetic mechanism, DNA methylation, also plays a critical role in learning and memory and several genes have been found to be hypomethylated in Alzheimers disease [3]. Hence, epigenetic drugs like the nutrients which donate methyl groups in the body resulting in methylation of DNA, S-adenosylmethionine and L-methylfolate, could help in the prevention and treatment of Alzheimers disease [3, 8]. Since, as alluded to above, epigenetics is thought to be involved in the pathogenesis of Alzheimers disease, epigenetic drugs are likely to act as disease modifying drugs in the management of this disease. In the light of the preceding information, I suggest that epigenetic drugs should be given due attention during the development of disease modifying drugs for the treatment of Alzheimers disease.

Inhibitory Effect of Nicorandil on the Contraction of Isolated Human Urinary Bladder Detrusor Muscle

This study was performed to determine whether the antianginal drug nicorandil relaxes isolated human detrusor muscle. Ten strips of detrusor muscle obtained from 10 pediatric patients who underwent surgery on the urinary bladder were contracted with 80 mM potassium chloride (KCl) before and after incubation with four concentrations of nicorandil (100, 200, 400 and 800 microM). The percent inhibition by nicorandil of the height and area under the curve (AUC) of KCl-induced contractions of the detrusor strips was calculated. The effect of glibenclamide (10 microM) on nicorandil (800 microM)-induced inhibition of KCl-induced detrusor contractions was also studied. Nicorandil caused a concentration-dependent inhibition of KCl-induced contractions of the detrusor strips. The percent inhibition of the height of KCl-induced contractions of the detrusor by nicorandil was significant at concentrations of 200, 400 and 800 microM. The percent inhibition of the AUC for KCl-induced detrusor contractions was significant at all four concentrations of nicorandil used. Glibenclamide reversed the inhibitory effect of 800 microM nicorandil on KCl-induced detrusor contractions. These results suggest that nicorandil inhibits KCl-induced contractions of isolated human detrusor muscle and may therefore be useful in clinical conditions requiring detrusor muscle relaxation.

Purkinje cell loss in autism may involve epigenetic changes in the gene encoding GAD

[1] Rout UK, Dhossche DM. A pathogenetic model of autism involving Purkinje cell loss through anti-GAD antibodies. Med Hypotheses 2008;71:218–21. [2] Yip J, Soghomonian J-J, Blatt GJ. Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: Pathophysiological implications. Acta Neuropathol 2007;113:559–68. [3] Peedicayil J. The role of epigenetics in mental disorders. Indian J Med Res 2007;126:105–11. [4] Schanen NC. Epigenetics of autism spectrum disorders. Hum Mol Genet 2006;15:R138–50. [5] Costa E, Dong E, Grayson DR, Guidotti A, Ruzicka W, Veldic M. Reviewing the role of DNA (cytosine-5) methyltransferase overexpression in the cortical GABAergic dysfunction associated with psychosis vulnerability. Epigenetics 2007;2: 29–36.

Inhibition by sildenafil of contractility of isolated non-pregnant human myometrium

Objective: To investigate the ability of sildenafil to inhibit the contractility of isolated non pregnant human myometrium. Materials and Methods: The inhibitory effect of three concentrations (3, 10, and 30 µM) of sildenafil on 55 mM KCl-induced contractility of isolated non-pregnant human myometrium was studied. The ability of the guanylyl cyclase inhibitor ODQ (10 µM), the adenylyl cyclase inhibitor MDL-12,330A (10 µM), the non-specific potassium channel blocker TEA (2 mM), and the calcium-sensitive potassium (BKCa) channel blocker iberiotoxin (100 nM) to reverse the inhibition of 10 µM sildenafil on KCl-induced myometrial contractility was also studied. Results: Sildenafil produced a concentration-dependent inhibition of KCl-induced myometrial contractility that was statistically significant at all three concentrations of sildenafil used. The inhibition by 10 µM sildenafil of KCl-induced myometrial contractility was not reversed by the concurrent administration of ODQ or MDL-12,330A. The inhibition of 10 µM sildenafil of myometrial contractility was partially reversed by concurrent administration of TEA and totally and significantly reversed by the concurrent administration of iberiotoxin. Conclusions: These results suggest that sildenafil inhibits the contractility of isolated non-pregnant human myometrium. The results suggest that sildenafil does so by opening BKCa channels.