Association of the functional serotonin transporter haplotype with familial form of obsessive compulsive disorder in Iranian patients

Objective: Several polymorphisms have been reported in the 5-HTTLPR of the serotonin transporter gene (SLC6A4). Family-based evidences for the association of 5-HTTLPR polymorphisms with OCD were previously reported but results were controversial. The present study investigated the possible correlation of SLC6A4 polymorphisms (5-HTTLPR, rs25532, rs25531) in Iranian OCD patients considering gender, age of onset, family history of psychiatric disorders, obsessive and compulsive subtypes and severities.

Methods: The included OCD patients fulfilled the criteria for DSM-IV-TR whom Y-BOCS score was more than 9. Blood samples (184 cases and 192 controls) were genotyped by means of PCR-RFLP.

Results: Mean of Y-BOCS scores of included patients was 20.1?±?0.69. Rs25532?CC genotype showed significant association with OCD in men and were detected more in the patients reported positive family history of psychiatric disorders but the other single loci (5-HTTLPR and rs25531) did not associate with OCD. Haplotype analysis showed significant association of 14-A variant with OCD and revealed the association of 14-A/14-A genotype with familial form of OCD.

Conclusions: The findings of this study showed the association of SLC6A4 variants with familial form of OCD and proposed stratified analyses in the genetic studies facilitate identification of genetic risk factors for this heterogeneous disorder.     

Mitochondrial Dysfunction and Biogenesis in Neurodegenerative diseases: Pathogenesis and Treatment

Neurodegenerative diseases are a heterogeneous group of disorders that are incurable and characterized by the progressive degeneration of the function and structure of the central nervous system (CNS) for reasons that are not yet understood. Neurodegeneration is the umbrella term for the progressive death of nerve cells and loss of brain tissue. Because of their high energy requirements, neurons are especially vulnerable to injury and death from dysfunctional mitochondria. Widespread damage to mitochondria causes cells to die because they can no longer produce enough energy. Several lines of pathological and physiological evidence reveal that impaired mitochondrial function and dynamics play crucial roles in aging and pathogenesis of neurodegenerative diseases. As mitochondria are the major intracellular organelles that regulate both cell survival and death, they are highly considered as a potential target for pharmacological‐based therapies. The purpose of this review was to present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) and the importance of mitochondrial biogenesis as a potential novel therapeutic target for their treatment. Likewise, we highlight a concise overview of the key roles of mitochondrial electron transport chain (ETC.) complexes as well as mitochondrial biogenesis regulators regarding those diseases.     

Evaluation of the anticonvulsant profile of progesterone in male amygdala-kindled rats

While there is clinical evidence that progesterone has anticonvulsant activity in women with complex partial seizures, previous studies on the anticonvulsant effect of progesterone in experimental animal models are inconclusive. Moreover, the effect of progesterone on seizure parameters in fully amygdala-kindled rats which best resemble complex partial seizures has not been evaluated. Therefore, in the present work the anticonvulsant effect of progesterone at doses of 10, 30, 60 and 75 mg/kg in fully amygdala-kindled male rats was studied. Only at the high and sedative dose of 75 mg/kg, progesterone suppressed behavioral seizures and afterdischarges elicited 10 min after intraperitoneal (i.p.) administration. Pretreatment with the progesterone antagonist, 17β-hydroxy-11β-(4-dimethylaminophenyl)-17-(prop-1-ynyl)-estra-4,9-dien-3-one (RU 38486) at the dose of 3 mg/kg did not inhibit the anticonvulsant activity of progesterone, while pretreatment with the GABA_A receptor antagonist, bicuculline (2 mg/kg) blocked the anticonvulsant effect of progesterone. Neither RU 38486 nor bicuculline had any effect on the seizure parameters. These findings suggest that only at large and sedative doses, progesterone has some anticonvulsant activity in male amygdala-kindled rats which may be partly mediated via the GABA_A receptor complex interaction.     

Involvement of the spinal serotonergic system in analgesia produced by castration.

The involvement of spinal serotonergic system in testosterone influence on formalin-induced pain was studied in male rats. Four weeks after castration, there was an analgesia in the late phase of formalin test that was reversed by intraperitoneal injection of testosterone enanthate (1 mg/kg) for 3 days. Flutamide (testosterone antagonist) produce analgesia in the late phase on intraperitoneal (10 mg/kg, IP) and intrathecal (60 microg/rat, IT) injections, but not on intracerebroventricular (60 microg/rat, ICV) administration. The antinociceptive effect of castration and IP flutamide (10 mg/kg) was abolished by pretreatment with 5,7-dihydroxytryptamine (5,7-DHT, 100 microg/rat, IT). IT-administered 5-HT (100 microg/rat) produced analgesia in the early and late phase of formalin test. Microdialysis sampling was used to characterize the extracellular concentration of 5-hydroxytryptamine (5-HT, serotonin) in the dorsal horn of the lumbar spinal cord. This technique demonstrated that levels of 5-HT were increased in 4-week castrated and IP flutamide (10 mg/kg) injected rats. The results may indicate that the analgesia produced by castration and flutamide administration is mediated through functional alteration in spinal cord serotonergic system.     

Changes in G proteins genes expression in rat lumbar spinal cord support the inhibitory effect of chronic pain on the development of tolerance to morphine analgesia

There are some reports regarding the inhibitory effect of pain on tolerance development to analgesic effect of opioids. The present study was designed to investigate whether the chronic formalin induced pain is able to reverse analgesic tolerance to morphine and to evaluate the expression of G(alpha i/o) and G(beta) subunits of G proteins in the context of chronic pain, development of morphine tolerance and their combination. Morphine tolerance was induced by chronic systemic (intraperitoneally, i.p.) or spinal (intrathecally, i.t.) administration of morphine to male Wistar rats weighing 200-240 g and analgesia was assessed using tail flick test. Chronic pain was induced by 4 daily intraplantar injections of 50 microl of 5% formalin. Lumbar spinal tissues were assayed for the expression of G(alpha i/o) and G(beta) proteins using "semiquantitative PCR" normalized to beta-actin gene expression. Results showed that chronic formalin induced pain could reduce and reverse the development of tolerance in rats that had received chronic (i.p. or i.t.) administration of morphine. Chronic administration of morphine did not change G(alpha i/o) gene expression, while chronic pain significantly increased its expression. The expression of G(beta), however, was increased after the chronic administration of morphine, but did not change after the induction of chronic pain. None of these increases were observed when morphine and formalin were administered at the same time. Due to synchronous development of morphine tolerance and changes in expression of G(beta), it may be concluded that the development of tolerance to analgesic effect of morphine is partially mediated by increase in G(beta) gene expression. The increase in G(alpha i/o) genes expression produced by chronic pain may facilitate the opioid signaling pathway and compensate for morphine-induced tolerance.     

Additive effect of dextromethorphan on the inhibitory effect of anti-NT4 on morphine tolerance

It has been proposed that opioid tolerance is a model of neuronal plasticity similar to learning and memory. Recent evidence suggests that neurotrophins may be involved in synaptic development and plasticity. Observations indicate that neurotrophin 4 (NT4) is required for the synaptic plasticity mediating both tolerance and memory. Also there are lines of evidence to indicate that NMDA receptors are involved in the neural plasticity underlying the development of opiate tolerance. Neurotrophins affect central transmission postsynaptically by enhancing NMDA receptor responsiveness. So we used the clinically available NMDA receptor antagonist, dextromethorphan, and the neurotrophin 4 antibody, anti-NT4, concomitantly and alone to investigate their effects on morphine tolerance. Tolerance was induced by injecting morphine (7 and 10 mg/kg i.p.) once per day for 4 days. Anti-NT4 (1 microg/rat i.c.v.) was administered 15 min before morphine. Results showed that chronic concomitant treatment of anti-NT4 with morphine in both doses inhibited the development of morphine tolerance. Also acute treatment of anti-NT4 significantly reversed the tolerance that was induced by morphine 7 mg/kg but failed to reverse the tolerance of morphine 10 mg/kg. Dextromethorphan in both doses (10 or 30 mg/kg) has an additive effect on the inhibitory effect of anti-NT4 on the reversal of morphine tolerance (7 mg/kg). These findings provide additional support for the hypothesis that NMDA receptor and NT4 may be involved in neural plasticity underlying opiate tolerance.     

X-linked agammaglobulinemia: a survey of 33 Iranian patients

In order to determine the clinical and laboratory features of X-linked agammaglobulinemia, the records of 33 male patients with XLA were reviewed during 22 years (1980-2002) in the Iranian referral center of primary immunodeficiency disorders. The patients' ages ranged from 20 to 360 months (median 113 months). The median age at the onset of the disease was 8 months and the median age of diagnosis was 48 months, with a median diagnosis delay of 33 months. Almost all of the patients presented common infectious diseases, which were: pneumonia, otitis, diarrhea, sinusitis, and arthritis. During the course of illness, infections in the respiratory tract, gastrointestinal tract, central nervous system, and musculoskeletal system were seen in 93.9%, 75.8%, 33.3%, and 21.2% of XLA patients, respectively. The most common complications of these patients were chronic infections in 75.8% of them, including: chronic otitis media, chronic sinusitis, chronic diarrhea, and bronchiectasis.     

Effect of regular intravenous immunoglobulin therapy on prevention of pneumonia in patients with common variable immunodeficiency.

BACKGROUND AND PURPOSE: Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder, which presents with hypogammaglobulinemia and recurrent bacterial infections. Patients with CVID have frequent and severe episodes of pneumonia. The standard intravenous immunoglobulins (IVIG) therapy has led to the reduction of pulmonary infections in these patients. The aim of this study was to evaluate the effectiveness of IVIG treatment in reducing the incidence of pneumonia in patients with CVID. METHODS: Twenty six Iranian patients with CVID whose diseases had been diagnosed at the Children Medical Center and had received regular IVIG for at least 9 months were selected. The numbers of episodes of pneumonia and hospital admissions were documented before and during treatment with IVIG. RESULTS: Of 26 patients with CVID, 80.5% had experienced pneumonia at least once before receiving immunoglobulin and 88.5% required hospital admission. After starting treatment with IVIG (mean treatment period, 41.5 +/- 35.4 months), the annual incidence of pneumonia significantly decreased from 80.5% to 34.6% (p=0.0017), and the rate of hospitalization from 88.5% to 46% (p=0.0025) .The incidence of pneumonia requiring treatment or hospitalization fell from 3.4 to 0.7 per year (p<0.0005). CONCLUSIONS: Regular IVIG therapy can significantly reduce the incidence of pneumonia and hospital admission due to infections in patients with CVID.