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Interactions between cannabinoids and phsopholipid metabolism in schizophrenia
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cN-CAM is a fragment of N-CAM 180 derived by proteolytic processing, and suggest that cN-CAM may be an indicator of neuronal damage or increased rates of synapse turnover.
B.204. A L T E R E D M E M B R A N E LEVELS IN SCHIZOPHRENIA
FATTY ACID
T. Easton, S.R. Hirsch, I. Das, L. Kidane, A.J. Richardson, B.K. Puri
Behavioural & Cognitive Science, ICSM Charing Cross, St. Dunstan's Road, London W6 8RP, England, UK Reduced levels of highly unsaturated fatty acid levels in erythrocyte, skin fibroblast and cerebral neuronal membrane phsopholipids have been reported in schizophrenia (Glen et al., 1994, 1996; Mahadik et al., 1996; Mahadik and Mukherjee, 1996). The aim of this study was to replicate and elaborate on these findings. The study included 14 patients with schizophrenia and 11 age- and sex-matched controls. A significantly lower concentration of total long-chain unsaturated omega-6 fatty acids in erythrocyte membranes was found in schizophrenia (p<0.02). The levels of 20:2n6 (p<0.005), arachidonic acid (p<0.03) and adrenic acid (p<0.008), an arachidonic acid metabolite, were also significantly lower in the patient group. Furthermore, total saturated (p<0.05) and monounsaturated (p < 0.003) erythrocyte membrane fatty acids were increased in schizophrenia while total polyunsaturated (p<0.04) fatty acids were reduced. These results support previous findings of reduced levels of fatty acids, particularly arachidonic acid, in schizophrenia, suggesting an abnormality of phospholipase A 2 enzymes.
References Glen A.I., Glen E.M., Horrobin D.F., Vaddadi K.S., Spellman M., Morse-Fisher N., Ellis K., Skinner F.S., 1994, Schizophrenia Research, 12, 53 61. Glen A.I.M., Cooper S.J., Rybakowski J., Vaddadi K., Brayshaw N., Horrobin D.F., 1996, Prostaglandins, Leukotrienes and Essential Fatty Acids, 55, 9-15. Mahadik S.P., Mukherjee S., 1996, Journal of Psychiatric Research, 30, 421 439. Mahadik S.P., Shendarkar N.S., Scheffer R.E., Mukherjee S., Correnti E.E., 1996, Prostaglandins, Leukotrienes and Essential Fatty Acids, 55, 65 70.
B.205. P H O S P H O L I P I D METABOLISM AND PERINATAL EVENTS WHICH LEAD TO INCREASED RISK OF SCHIZOPHRENIA David F. H o r r o b i n
Laxdale Research, Kings Park House, Laurelhill Business Park, Stirling, Scotland FK7 9JQ Certain perinatal events appear to increase the risk of later schizophrenia. A consensus is emerging that the two most
important factors are pre-eclampsia and perinatal hypoxia. However, the great majority of infants exposed to those events do not develop schizophrenia. A likely explanation is that the perinatal events increase the risk of schizophrenia only in those who have a predisposing biochemical abnormality. The phospholipid hypotheses proposes that defects in the metbolism of highly unsaturated fatty acids (HUFAs), particularly omega-3 HUFAs, at the Sn2 position of neuronal phospholipids are important in schizophrenia. One of two important abnormalities may be overactivity of phsopholipase Az which removes these HUFAs from phospholipids. There is now a great deal of evidence from many laboratories that hypoxia and ischemia activate brain phsopholipase A 2. Those with a tendency to elevated PLA: activity would thus be more susceptible to damage. Several studies have now demonstrated that mothers and infants in pre-eclampsia affected pregnancies have substantially reduced levels of omega-3 fatty acids which are required for brain development. Again this would be expected to be more damaging against a background of the pre-existing phospholipid abnormalities. Thus the phospholipid concept can explain why some infants but not others are at increased risk of schizophrenia following perinatal complications.
B.206. I N T E R A C T I O N S BETWEEN CANNABINOIDS AND PHSOPHOLIPID METABOLISM
IN SCHIZOPHRENIA
David F. H o r r o b i n
Laxdale Research, Kings Park House, Laurelhill Business Park, Stirling, Scotland FK7 9JQ Cannabis use is associated with increased risk of initial breakdown or relapse in people at risk of schizophrenia. Cannabis may have more marked effects in those at risk of schizophrenia than in normal individuals. The phospholipid concept of schizophrenia suggests two hypotheses for the interaction between cannabis and schizophrenia. First, the endogenous ligands for cannabis receptors are derivatives of arachidonic acid such as anandamide and 2-arachidonyl glycerol. In schizophrenia, arachidonic acid turnover is altered and arachidonic acid in membrane phospholipids may be depleted. Thus interactions between exogenous cannabinoids and neurons would be expected to be different in patients with schizophrenia. Second, one of the abnormalities postulated by the phospholipid hypothesis is partially impaired function of a group of enzymes known as fatty acid coenzyme-A-ligases (FACL) also known as acyl-CoA or arachidonyl-CoA synthetases. Several years ago Hokin found that cannabinoids inhibit these enzymes, by a mechanism not involving the cannabinoid receptor. Such an inhibitory effect would be expected to be more severe in individuals with partially impaired FACL function, thus helping to explain the potentially severe effects of cannabis in people at risk of schizophrenia.
cN-CAM is a fragment of N-CAM 180 derived by proteolytic processing, and suggest that cN-CAM may be an indicator of neuronal damage or increased rates of synapse turnover.
B.204. A L T E R E D M E M B R A N E LEVELS IN SCHIZOPHRENIA
FATTY ACID
T. Easton, S.R. Hirsch, I. Das, L. Kidane, A.J. Richardson, B.K. Puri
Behavioural & Cognitive Science, ICSM Charing Cross, St. Dunstan's Road, London W6 8RP, England, UK Reduced levels of highly unsaturated fatty acid levels in erythrocyte, skin fibroblast and cerebral neuronal membrane phsopholipids have been reported in schizophrenia (Glen et al., 1994, 1996; Mahadik et al., 1996; Mahadik and Mukherjee, 1996). The aim of this study was to replicate and elaborate on these findings. The study included 14 patients with schizophrenia and 11 age- and sex-matched controls. A significantly lower concentration of total long-chain unsaturated omega-6 fatty acids in erythrocyte membranes was found in schizophrenia (p<0.02). The levels of 20:2n6 (p<0.005), arachidonic acid (p<0.03) and adrenic acid (p<0.008), an arachidonic acid metabolite, were also significantly lower in the patient group. Furthermore, total saturated (p<0.05) and monounsaturated (p < 0.003) erythrocyte membrane fatty acids were increased in schizophrenia while total polyunsaturated (p<0.04) fatty acids were reduced. These results support previous findings of reduced levels of fatty acids, particularly arachidonic acid, in schizophrenia, suggesting an abnormality of phospholipase A 2 enzymes.
References Glen A.I., Glen E.M., Horrobin D.F., Vaddadi K.S., Spellman M., Morse-Fisher N., Ellis K., Skinner F.S., 1994, Schizophrenia Research, 12, 53 61. Glen A.I.M., Cooper S.J., Rybakowski J., Vaddadi K., Brayshaw N., Horrobin D.F., 1996, Prostaglandins, Leukotrienes and Essential Fatty Acids, 55, 9-15. Mahadik S.P., Mukherjee S., 1996, Journal of Psychiatric Research, 30, 421 439. Mahadik S.P., Shendarkar N.S., Scheffer R.E., Mukherjee S., Correnti E.E., 1996, Prostaglandins, Leukotrienes and Essential Fatty Acids, 55, 65 70.
B.205. P H O S P H O L I P I D METABOLISM AND PERINATAL EVENTS WHICH LEAD TO INCREASED RISK OF SCHIZOPHRENIA David F. H o r r o b i n
Laxdale Research, Kings Park House, Laurelhill Business Park, Stirling, Scotland FK7 9JQ Certain perinatal events appear to increase the risk of later schizophrenia. A consensus is emerging that the two most
important factors are pre-eclampsia and perinatal hypoxia. However, the great majority of infants exposed to those events do not develop schizophrenia. A likely explanation is that the perinatal events increase the risk of schizophrenia only in those who have a predisposing biochemical abnormality. The phospholipid hypotheses proposes that defects in the metbolism of highly unsaturated fatty acids (HUFAs), particularly omega-3 HUFAs, at the Sn2 position of neuronal phospholipids are important in schizophrenia. One of two important abnormalities may be overactivity of phsopholipase Az which removes these HUFAs from phospholipids. There is now a great deal of evidence from many laboratories that hypoxia and ischemia activate brain phsopholipase A 2. Those with a tendency to elevated PLA: activity would thus be more susceptible to damage. Several studies have now demonstrated that mothers and infants in pre-eclampsia affected pregnancies have substantially reduced levels of omega-3 fatty acids which are required for brain development. Again this would be expected to be more damaging against a background of the pre-existing phospholipid abnormalities. Thus the phospholipid concept can explain why some infants but not others are at increased risk of schizophrenia following perinatal complications.
B.206. I N T E R A C T I O N S BETWEEN CANNABINOIDS AND PHSOPHOLIPID METABOLISM
IN SCHIZOPHRENIA
David F. H o r r o b i n
Laxdale Research, Kings Park House, Laurelhill Business Park, Stirling, Scotland FK7 9JQ Cannabis use is associated with increased risk of initial breakdown or relapse in people at risk of schizophrenia. Cannabis may have more marked effects in those at risk of schizophrenia than in normal individuals. The phospholipid concept of schizophrenia suggests two hypotheses for the interaction between cannabis and schizophrenia. First, the endogenous ligands for cannabis receptors are derivatives of arachidonic acid such as anandamide and 2-arachidonyl glycerol. In schizophrenia, arachidonic acid turnover is altered and arachidonic acid in membrane phospholipids may be depleted. Thus interactions between exogenous cannabinoids and neurons would be expected to be different in patients with schizophrenia. Second, one of the abnormalities postulated by the phospholipid hypothesis is partially impaired function of a group of enzymes known as fatty acid coenzyme-A-ligases (FACL) also known as acyl-CoA or arachidonyl-CoA synthetases. Several years ago Hokin found that cannabinoids inhibit these enzymes, by a mechanism not involving the cannabinoid receptor. Such an inhibitory effect would be expected to be more severe in individuals with partially impaired FACL function, thus helping to explain the potentially severe effects of cannabis in people at risk of schizophrenia.