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I e e Invest Clin 36 (Sup. 2): 221-224. 1995 IIlvest eh 14(2): 8~86, 1973 Venezuelan equine EncephalomyeHtis virus infection: Effect on Dopamine metabolism of mouse brain. Preliminary communication. Ernesto Bonilla and Slavia Ryder: Instituto de Investigaciones Clínicas, Facultad de Medicina. Universidad del Zulla. Apartado 1151. Maracaibo 400 l-A, Venezuela. Abstract. Inoculation of VEE virus to mice produces an increase in bratn dopamine and homovantllic acid. This rise possibly results from an increase in the levels of L-Tyrosine hydroxylase. Infecci6n con el virus de la encéfalomielitis equina venezolana: efecto sobre el metabolismo de la dopamlna en el cerebro del rat6n. COmunlcaci6n preliminar. Invest cUn 14(2):82-86. 1973. Resumen. En ratones inoculados con el virus de la EEV se produce un incremento de la concentración de dopamina y del ácido homovanílico en el cerebro. Este aumento posiblemente es debido a una elevación en los niveles de la hidrox:1lasa de la tirosina. It Is a known fact that Parkinso n's disease can follow an acute en cephalitis. Although the majority of cases are Idiopath1c. It has been suggested that those patients have experienced subcllnical encephali tis (3). As a speciftc dopamine deft ciency has been demonstrated in Parkinson's disease (4) we conside red itof interest to study the effects of Venezuelan equine encephalom yel1tis (VVE) virus infectton on dopa mine metabol1sm specially followtng recent reports suggesting that spe- cific effects on monoamine metabo lism might be the consequence of virus infection (7-9). Albino mlce. three to four weeks old, were Inoculated lntraperi toneally with 0.03 (contatning 100 LD50) of the Guajira strain of VEE virus (lO). The antmals were killed by cervical dislocation on the sixth day after inoculation, when paraly sis of the ltmbs was evident. Brains were weighed and stored frozen at -70°C. unt1l analysed for dopamine (DA) and homovanilllc acid (INA) Bonilla - Ryder 222 content (11). The brains of three not betng found in several bacterial mice were pooled for each determi nation. Sham inoculation was omit ted because no difference was found in determinations on non-1nocu lated mice which thereafter were used as controIs. As shown in table 1, VEE virus infection produces an increase in brain DA and HVA concentration {p<O.OOl).lfthe animals are harves ted (in groups of 27 mice) and tested for contents of DA and HVA daily after inoculation, the 1ncrease is evi dent beginning on day 5, when most of the mice show signs of encepha litis (tremor, ataxia, paralys1s of the limbs), but not before, suggesting a possible relationship between mul tiplication ofVEE virus and concen tration of DA and HVA. Such a rela tionship has been found for HVA and herpes simplex virus (7), Encephalitis developed after in tracerebral inoculation of Schlso trypaDum cruzlin m1ce did not pro duce any change in the bratn levels ofDA and HVA (Bon1lla L and Bon1lla E, unpublished results). It looks as if such changes are typ1cal of diffe rent viral infections s1nce they have and protozoal infections examl ned(9). The observed rise in brain DA and HVA concentrations could be explatned in terms of an increase in the levels of tyroslne hydroxylase, the rate limiting step in catechola mine synthes1s (6). The increment in enzyme protein could be due to an increased synthesis and/or to a re duction of its rate of proteolytic de gradation. The rise in HVA concen tration was smaIler when compared with the 1ncrease in DA: therefore a retarded outflow of HVA from brain to blood 1s probably not the cause of our find1ngs. On the contrary, an tnflammatory process tends to acce lerate the transport through the blood-bratn barrier (1). This effect would explatn the differences obser ved in the lncrements ofDA and HVA seen in VEE virus infection: nor malIy, a high productlon of DA wiIl be accompan1ed by a similar increa se of HVA (provided there is not an inhib1tion of monoaminooxidase). lf in VEE virus lnfection there Is an increase outflow of HVA together with an increase production of DA. TABLE 1 CONCENTRATlON OF DOPAMINE AND HOMOVANILIC ACID IN BRAINS OF MICE INFECTED WITH VENEZUELAN EQUINE ENCEPHALOMYELmS VIRUS. THE MICE WERE KILLED ON THE SIXTH DAY AFrER INOCULATlON. Groups N° of CONTROLS INFECTED mice 129 129 Dopamine (ug/g of brain) 0.69 ± 0.10 1.52 ± 0.12 Homovanll1c Acid (ug/g of bratn) 0.12 ± 0.01 0.18 ± 0.02 Investigación Clinlca 36 (Sup. 2): 1995 223 VEE virus lnfectlon. Dopamlne metabolismo the levels in brain HVA, although high. will not reach the higher va Iues observed if an 1mpairment of the outllow were not presento Our resuIts could also be explai ned in terms of a decrease in the levels of dopamine-~-hydroxylase. However, it 1s known that different pharmacological or physiologic stresses which produce increased neuronal actlvity elevate tlssue le veIs of dopamine-~-hydroxylase and tyrosine hydroxylase (5). Besides. in spite of the large amount of dopami ne-~-hydroxylase normally found in the neostriatum, the noradrenalin content in this regíon Is relatlveIy Iow. This contrast with the fact that 80% of cerebral dopamine Is Iocated in the striatum (2), suggesting that the main pathway in this structure Is not concerned with the formatlon of noradrenaline. Thls be1ng the case, any important lncrease in brain dopamine Is not necessar1ly due to a decrease in dopamine- ~ hydroxylase. Experiments are in progre ss to determine whether the biochemical changes are l1mlted to DA and HVA or to other monoamines, and assays oftyrosine hydroxylase and dopami ne-beta-hydroxylase duringviral in fecUon wiIl be done to test our hypothesis. Whatever the mechanism un derlytng these observatlons, 1t Is clear that VEE virus infectlon pro duces an lncrease in the actlvity of dopaminergic neurons. This effect could initlate the sequence of events leading to a destructlon and loss of Vol. 36 (Sup. 2): 221-224. 1995 these cells and finally. to the deve lopment of parkinsonism. AGRADECIMIENTO Al técnico químico Carlos Val buena por su excelente trabajo téc nico. REFERENCIAS BmUOGRAFICAS 1 2 BAKAY L: The cerebral uptake of tri tiated tetracycline from blood and cerebrospinal fluid under normal con ditions and in experiméntal pneumo coceal meningitis. J Neuropath 21: 424-436. 1962. BERTLER A, ROSENGREN E: Ocurrence and distribution of dopamine in brain and tissues. Exper ientia (Basel) 15: 10-11,1959. 3 CALNE DB: Parkinsonism: physiol ogy, pharmacology and treatment. (Amold E, 00) London. 1970, p 25. 4 EHRINGER H, HORNYK1EWICZ O: Verteilung von Noradrenalin und Dopamin (3 Hydroxytyramin) im Ge him des Menschen und ihr Verhalten bei Erkrankungen des extrapyrami dalen systems. Klin Wochschr 38: 1236-1239, 1960. 5 KOPIN lJ: Control of synthesis, trans port and relase of dopamine-betahy droxylase and tyrosine hydroxylasee, in New Concepts in Neurotransmitter Regulation (Mandell AJ, ed) Nex York, Plenum Press, 1973, pp 21-31. 6 LEVITT M, SPECTOR S, SJOERD SMA A, UDENFRIEND S: Elucida tion of the mte limiting step in NE biosynthesis in the perfusoo guinea pig heart. J Pharmacology 148: 1-8,1965. Bon1lla - Ryder 224 7 8 9 LYCKE E, ROOS BE: Fffect on the monoamine metabolism of mouse brain by experimental herpes infec tian. Experientia(Basel) 24: 687-689, 1968. LYCKE E, MODIGH K, ROOS BE: The monoamine metabolism in viral encepbaJítides of me mouse. 1. Vi rological and biocbemical results. Brain Res 23: 235-246, 1970. LYCKE E, ROOS BE: Tbe monoamine metabolism in viral encepbalilides of the mouse. 11. Tum over of monoamines in mice infected 10- 11- witb herpes simplex virus. Brain Res 44:603-613,1972. SOTO-ESCALONA A, FINOL LT, RYDER S: Estudio de un brote de encefalitis venezolana en el Distrito Páez, Estado Zulia, en octubre de 1968. InvestClin 10(31): 45-57.1969. SPANO PF, NEFF NH: Procedure for simultaneous determination of dopamine, 3-metboxy -4-bidroxy pbenylacetic acid, and 3,4- di bidroxypbenylacetyc acid in braín. Anal Biochem42: 113-118, 1971. Investigación Clínica 36 (Sup. 2); 1995