Download Venezuelan equine EncephalomyeHtis virus infection: Effect on

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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.
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Investigación Clínica 36 (Sup. 2); 1995