subtlepangs

Abstract

The pathophysiology of bipolar disorder (BD) is poorly understood. An emerging body of evidence points to impairments in neuroplasticity, cell resilience and neuronal survival as the main neuropathological correlates of BD. It has been suggested that inflammatory cytokines, particularly TNF-α may play a critical role in this process. In the present review we examine the evidence suggesting that TNF-α regulates apoptotic cascades which may be related to neuronal and glial loss in BD. Current evidence suggests that an increase in serum levels of TNF-α takes place during manic and depressive episodes. The present article reviews the therapeutic implications of TNF-α signaling pathways involvement in the pathophysiology of BD.

Abbreviations: ADNF, Activity-Dependent Neurothrophic Factor; BD, Bipolar Disorder; BDNF, Brain Derived Neurothrophic Factor; CNS, Central Nervous System; CRH,Corticotrophin-releasing hormone; CSF, Cerebral Spinal Fluid; TNF-α, Tumoral Necrosis Factor-α; I-κB, Inhibitor of κB; MMSE, Mini Mental State Examination; NF-κB, Nuclear Factor-κB; NGF, Nerve Growth Factor; SOD, Superoxide dismutase.

Keywords: Bipolar disorder; Cytokines; Mood disorders; NF-κB; TNF-α

We compared the effects on the ratio of plasma tryptophan to large neutral amino acids (trp:LNAA) of two different carbohydrate meals (sucrose or starch, 120 g) and a contrasting meal of fat + protein given at breakfast to 10 healthy adults. Plasma glucose and insulin were also measured. The trp:LNAA ratio rose after both carbohydrate meals (p less than 0.001). Glucose and insulin peaks were higher after sucrose than starch, and trp:LNAA rose correspondingly higher (sucrose +34% and starch +20%, p less than 0.05). The ratio declined 45% after the fat + protein meal. At 180 min, absolute ratio values were twofold higher after carbohydrate (sucrose 0.133 and starch 0.127) than after fat + protein (0.057). Similar results were found with the same meals given in the evening. Our results suggest that high-carbohydrate meals have an influence on serotonin synthesis. We predict that carbohydrates with a high glycemic index would have a greater serotoninergic effect than carbohydrates with a low glycemic index.  

Reports concerning changes in plasma neurotransmitter values that result from dietary manipulations have not been published so far. The influence of various meal compositions on platelet-poor plasma (PPP) serotonin (5-HT) and norepinephrine (NE) levels was investigated. Healthy volunteers were subjected to three test meals: a carbohydrate-rich meal (86% carbohydrates), a protein-rich meal (70% protein), and a fat-rich meal (92% fat). After a carbohydrate-rich meal, PPP 5-HT values increased significantly (4.47-fold, P less than .02), whereas a smaller increase (1.66-fold, P = NS) was observed after a fat-rich meal. These effects on PPP 5-HT values could be correlated with insulin plasma levels. A protein-rich meal significantly reduced (P = 0.0011) PPP 5-HT to 28% of initial values, despite an increase in plasma insulin levels. This study has shown that (1) changes in meal compositions influence PPP 5-HT and, to a lesser extent, NE values; (2) the resulting changes in PPP 5-HT levels parallel those reported for brain neurotransmitters; and (3) these results seem to indicate that PPP 5-HT levels may be a model for brain synthesis and release of 5-HT.

Researchers have reported a stimulatory effect of carbohydrate-rich intake on platelet-poor plasma (PPP) serotonin (5-HT) levels in healthy human subjects. Dietary manipulation may serve as a safer and less invasive means than pharmacologic challenge to provoke serotonergic responsivity in studies of schizophrenia. In the present study, we used the carbohydrate-rich meal test as an indicator of 5-HT activity in 12 patients with chronic schizophrenia maintained for at least 6 months on clozapine. PPP 5-HT levels were measured at baseline and at 1, 2 and 3 h after administration of the test. Findings were compared with those in schizophrenic patients treated with classic antipsychotic agents for the same duration. The maximal PPP 5-HT response was reached 120 min after meal administration in the clozapine-treated group and 60 min after in the classic antipsychotic-treated group (P<0.05 vs baseline for both). The 5-HT level (as percentage of baseline) at 60 min was significantly lower in the clozapine-treated group (P<0.02), as were individual PPP 5-HT peak values (P<0.05). The individual time to reach the peak response was similar in the two groups. Our results indicate that in patients with chronic schizophrenia 5-HT responsivity to the natural challenge of carbohydrate-rich meals is lower in those treated with clozapine than in those given classic antipsychotic agents. Values in both groups were lower than those in an appropriate historical comparative group of healthy subjects. We suggest that both clozapine and classic antipsychotic agents suppress serotonergic system sensitivity, but to a different degree. Copyright 2001 John Wiley & Sons, Ltd.

Antibodies to serotonin in serum were investigated by ELISA in patients with paranoid schizophrenia (N=27), schizoaffective psychosis (N=38), depression (N=67),Alzheimer’s disease (N=21), chronic alcoholism (N=43), rheumatoid arthritis (N=25), and multiple sclerosis (N=16), and in healthy volunteers (N=60). Increased antibody reactivity to serotonin was found in schizoaffective psychosis, chronic alcoholism, and rheumatoid arthritis. Decreased antibody reactivity to serotonin was found in multiple sclerosis and depression. These anti-serotonin antibodies belong to the class of so-called natural autoantibodies. Alterations of these natural autoantibodies could indicate a disturbance to the immune system. It is possible that these antibodies could also influence receptor function. Autoantibodies to neurotransmitters in a wide spectrum of psychiatric disorders have not previously been reported.

Abstract

Unexplained diarrhoea is a frequent indication for gastroenterologic referral, and after full investigation the most common final diagnosis is irritable bowel syndrome (IBS). Some patients with IBS describe an acute onset of symptoms following infective gastroenteritis. Postinfective IBS affects 7% to 31% of individuals infected, and appears to be a nonspecific response to injury which has been reported following Salmonella-, Campylobacter-, and Shigella-related IBS. The strongest risk factor for developing postinfective IBS is severity of the initial diarrhoea illness, but toxigenicity of the infected bacteria, age <60 years, and female sex also are important risk factors. Adverse life events, hypochondriasis, and depression are also important, as is increased enteroendocrine cell and lymphocyte numbers in rectal biopsies. Postinfective IBS and IBS with diarrhoea without an infectious onset both show increased postprandial release of serotonin, whilst constipated patients show a depressed release. Several studies suggest impairment of the serotonin transporter in IBS, which in animal studies has been shown to occur following a range of inflammatory insults. Clinical conditions with an inflammatory basis, such as coeliac and Crohn disease, also are characterised by excess postprandial serotonin release. Several studies report evidence of low-grade inflammation in IBS with diarrhoea. However, reliable markers of low-grade inflammation that may predict response to serotonin antagonists or other anti-inflammatory agents remain a goal for future research.

Objectives: Serotonin is supposed to modulate interactions between the nervous system and the immune system. For example, knocking out SERT influences the susceptibility to inflammatory infiltration in mice (Hofstetter 2005). Furthermore, the SERT inhibitor fluoxetine has neuroprotective properties in MS (Lo 2008). Finally, depression and fatigue are influenced by serotonergic mechanism and often occur in MS patients. The aim of our study was therefore to investigate SERT availability with [C-11]DASB and PET in MS.

Methods: 20 patients with MS (16 females, 40±11yrs, drug-naïve, 4 under immune modulatory therapy) and 23 healthy volunteers (HC, 11 females, age 36±9yrs) underwent 90-min dynamic PET after IV injection of 430 MBq [C-11]DASB. Distribution volume ratios (DVR) were generated using the multilinear reference tissue model with two parameters (Ichise 2003). SPM2 (30 voxels, p<0.001, uncorr.) and VOI analysis after co-registration of DVR maps with MRI were performed. Fatigue and depression were rated by Würzburger Erschöpfungsinventar bei MS (WEIMuS) and Beck Depression Inventory (BDI), respectively. For correlation analyses and group comparison, age, smoking habitus, and body mass index served as co-variates.

Results: Compared with HC, DVR in MS was significantly reduced in the hypothalamus (2.26±0.43 vs 2.54±0.33; p=0.03). There were further trends toward a significant reduction in the hippocampus, the thalamus, the insula, and the anterior cingulate cortex (0.05< p<0.1). Despite MS patients had significantly higher WEIMuS (24±18 vs 4±6, p<0.001) and BDI values (6.2±6.9 vs 1.4±2.4, p=0.005), neither BDI nor WEIMuS correlated significantly with DVR in any brain region.

Conclusions: In patients with MS, there is lower SERT availability in limbic and paralimbic regions reaching significance in the hypothalamus. However, an association between a serotonergic dysbalance and the occurrence of fatigue/mood disturbances in MS has not been proven yet by means of our data

T h e   e f f e c t   o f   s e r o t o n i n   o n  t h e   u l t r a s t r u c t u r e   o f  t h e   w h i t e   m a t t e r   i n   t h e   CNS  o f  d o g s   w a s   s t u d i e d .  

I n t r a c i s t e r n a l   i n j e c t i o n   o f  t h e   a m i n e   (6  ~zg i n   0 . I   m l   p h y s i o l o g i c a l   s a l i n e )   l e d   t o   c o n s i d e r a b l e  

d i s t u r b a n c e s   i n   t h e   m y e l i n   a n d   g i l a   in  r e g i o n s   o f   t h e   w h i t e   m a t t e r   o f  t h e   s p i n a l   c o r d   a d j a c e n t   t o  

t h e   c e r e b r o s p i n a l   f l u i d   c h a n n e l s .   L o s s   o f   t h e   r e g u l a r   s t r u c t u r e   a n d   s e p a r a t i o n   o f  t h e   l a m e l l a e  

o f  t h e   m y e l i n   w i t h   r u p t u r e   a n d   l y s i s   o f  t h e   m y e l i n   s h e a t h   a n d   d e m y e l i n a t i o n   w e r e   o b s e r v e d .  

V a c u o l a r   d e g e n e r a t i o n   w a s   o b s e r v e d   i n   t h e   o l i g o d e n d r o c y t e s ;   t h e   a s t r o e y t e s   w e r e   v i r t u a l l y  

u n c h a n g e d .   A f t e r   l o c a l   l n t r a c e r e b r a l   i n j e c t i o n   o f  t h e   a m i n e   (2  lzg i n   0.01  m l   p h y s i o l o g i c a l   s a -  

l i n e )   s i m i l a r   d i s t u r b a n c e s   d e v e l o p e d   in  t h e   w h i t e   m a t t e r   o f   t h e   c e r e b r a l   h e m i s p h e r e s ,   b u t   w i t h  

f e a t u r e s   o f   a n   i n f l a m m a t o r y   r e a c t i o n   in  t h e   l a t e   s t a g e s   o f   t h e   i n v e s t i g a t i o n .   I n   c o n t r o l   a n i m a l s  

w h i c h   r e c e i v e d   i n j e c t i o n s   o f   p h y s i o l o g i c a l   s a l i n e ,   c h a n g e s   a p p e a r e d   l a t e r   a n d   o n l y   i n   t h e   g l i o -  

c y t e s .   I t   i s   c o n c l u d e d   t h a t   s e r o t o n i n   h a s   t h e   p r o p e r t y   o f   i n j u r i n g   m y e l i n   a n d   g l i a .  

K E Y   WORDS:   s e r o t o n i n ;   u l t r a s t r u c t u r e   o f   t h e   CNS;   m y e l i n ;   g i l a ;   d e m y e l i n a t i o n .  

S u m m a r y .  P l a t e l e t  s e r o t o n i n  u p t a k e  wa s  s t u d i e d  in 20 p a t i e n t s  

w i t h   m u l t i p l e   s c l e r o s i s   (MS )   i n   a c u t e   r e l a p s e   a n d   in  20  a g e -  

a n d   s e x - m a t c h e d   c o n t r o l s .   W h i l e   t h e r e   wa s   n o   d i f f e r e n c e   i n  

t h e  m a x i m u m  v e l o c i t y  o f  t h e  u p t a k e ,  M i c h a e l i s  c o n s t a n t s  w e r e  

s i g n i f i c a n t l y  h i g h e r  a n d   c o r r e l a t e d  p o s i t i v e l y  wi t h  t h e   D i s a b i l -  

i t y  S t a t u s  S c a l e  s c o r e .   T h e   r e s u l t s  s u g g e s t  a  c o m p e t i t i v e  b l o c k  

o f  t h e   s e r o t o n i n  u p t a k e   s i t e s  i n  p l a t e l e t s  o f  M S  p a t i e n t s .  

K e y  wo r d s :  M u l t i p l e  s c l e r o s i s  -  S e r o t o n i n  u p t a k e   -  P l a t e l e t s  - 

D i s a b i l i t y  S t a t u s  S c a l

Abstract. Positive symptoms in schizophrenia decrease the requirement for REM sleep and reduce its pressure, while negative symptoms increase the need for REM sleep. This need cannot be satisfied because REM sleep in schizophrenia is functionally insufficient. This insufficiency may relate to the decreased melatonin level. Melatonin treatment restores REM-sleep functional efficiency in patients with different mental disorders, probably also in schizophrenia. There are some signs that melatonin inhibits brain dopamine systems that are active in wakefulness and that stimulate the dopamine system responsible for REM sleep-dreams sufficiency.