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Thyrotropin-releasing hormone (TRH) increases morbidity and mortality in the gerbil stroke model
N e a r e s d e n c e Letters, 33 (1~2) 2~9-$07
299
Elsevier Scientific Publishers !re]~a~ Ltd.
CHAR~:(:J~ -:HAHNAN, fir.-and A N G E L R . GAKCIfA§': " C e n t e r , Fort G o r d o n , GA-:JOgOf tU, S ~ A J - '
"
"
"
-f
The gerbilmodelfor stroke, using permanent unilateral carotid artery occlusion and restriction of the contralateral artery, was used to assess exogenous thyrotr,~pin-relea~ng hormone (TRH~ ]0 mg/kg, i.p.) effect on: cerebral ischemia: TRH innncdiately post~occlusion, compared to saline controh, significantly increased m o ~ t y (P: = 0.ff25). This was supported by worsening refle.~ted in the stroke index and time to death, Thyrotropin (0. i IU, i.p,) in the same model was without effect. These surprising results were unexpected due to the beneficial response to ~he pharmacologicaily related naloxone.
Thegerbil. has been used extensively as a model for studying the pathophysiology of cerebral infarction [5,9, 14] ever since the discovery by Levine and Payan [17] of this animal's unique susceptibility to cerebral ischemia. The gerbil lacks an artery communicating the major anterior blood supply from the internal carotid artery with the posterior basilar arterial blood supply [3]° This allows a relatively simple common carotid artery occlusion to produce closed head cerebral ischemi~ for experimental study. Using this model, a number of investigators have examined the value of: e x ~ m e n m t drug therapies to improve the morbidity or mortality consequent to the induced isehemia [13, 15, 191.Some agents such as phenoxybenzami~e [21], atropine, thiosernicarbazide, pheny*oin, theophylline [15] and an~nophylline [20] have proven to be dele~:erious to the recovery or to the amelioration of neurolo#c damage. Thyrotropin-releasing hormone (TRH) was chosen for evalu:~tion in the gerbil stroke model because of its beneficial effects in a s#nal trauma model in cats [7]. The rationale also included the improvement of neurologic deficits in~ the rgerbil stroke model by the pharmacolo#cally related compound, naloxone * In conducting the research described in this report, the investigators adhered ~.othe 'Guide for the Care and Use of Laboratory Animals', as promulgated by the Commfftee on .~,evision of the Guide for La~ra~ory. Animal FaCilities and C~/re, of the Institute of Laboratory Animal F~esourees, National :The:~piiiions or asse;;fions contained h~,~eirfare the private views of the authors and ~re rtot to be constrtted as 0ff'~:ial~of:as ~:eflecdng the views of th~ Department of Army or Department of Defense° 0304-3940/82/0(KAk-00f~/$ 02.75 © 1982 Elsevier $cie~~tific Publishers Ireland Ltd.
34)0 ,
.
•
++
.
+':
+r
¸ /'+,
,
[12]. Naloxone-induccd improvement in. the c~: s p ~ tramim mode!i [6+ 8] +hmd originally led to ,the tri~ of TRH i n that model |7]+,TRH hm+a+m+i~y0feff~+ts when administeredsystemically besidesthe release+of+th~ot~op~nC~H)[4]L, T h ~
one possesses. It s ~ m e d logicalto extendthe ¢~m~natio~ oftl~¢,~fiCi~l~effe~t repo ted to be produc+d by TRH therapy, It was very ~ Z i s ~ i t o , fi~d z ~ , ~ o u S i , ~ o ~ oF~m0rbi~ty~i~d~I mortality in TRH-tremed exper~ental, animMs 'ilt~t h e i ~ . ~ nti ~udy/:i ~:~:~:/+Y:I.~:}i~!Yl;:!~:= Thirty Meriones ungu~culatus, Turn. (MO .!~., .mah~talned ona reversedJ2~hl!gh~ t, 12-h dark cycle, had their left commoncarotid artery occluded.,and right common carotid restricted under ketamine anesthesia (50 mg/kg) between 08.30and 10.30 h [10]. Immediately after suturing the: exnployed midline incision, either TRH:I~10 mg/kg, i.p. in 2 mg/ml sterile saline+ Sigma Chemicai) or an equal volumeofsal~+Me was injected alternately in occludedgerb~lS. Animals were ~ami~ia~:r07,~:~!6~00 ~'ld 23.00rh andwere evaluated ngurolOgically a s describ~ by MCGra~ [!9]~:~t672 h post ligation. At the end of one week, the TRH group had 12 (80~/0) mortalities, whereas the saline control group had 6 (40¢/0). The difference is significant by the chi-square test (P = 0.025). The median survival time forthe control group was greater than 72 h and for the TRH group was 31 h. :['he neu.~¢logical evaluation is summarized in Fig. 1 as the mean stroke index at each 8 h interval. The highe~ the Stroke, index, the worse the neurological condition of the animal. A measure of time-to-death (Lee-Desu statistic, P = 0.0728)and comparison of the stroke indices at: the 9 observation times (Wald-Wolfowitz Runs Tests, P < Oo02), also indicated that the t~,~o groups were different (these non-parametric computer analy~es are pastor ther SPSS Batch System softwareL Oneweck after oc¢lusion,allsUr*d~ing~ animals ~ere fixed by pcrfusion with Carsons' buffered forma!in and,: processed~ for fight microscopy, One of the 3 survivors :in the TRH group and 2 of~the 9su~ors~ir~ the control group had histologicallydemonstrat¢fl cetebraI~nfarctions.: ' Because of the unexpectedly devastating effect of ~RH on thei~hemicanimals~ the possibility of idiosyncratic reaction was conside~red. TR]~ in cquivalent~dos~: was injected into normal gerbils withoutunusualeffec~, DeSpite the limited evidence for a pathological effect o~' thyrotropin (TSH)in cerebral ~schemia [27], a~dose of 0.1 international unit of TSH was injected intrapcritoneally into each of a group of 15 occluded gerbils with 15 occluded saline controls. Mortality figures did not indicate a~y effecL
Although the production of hyi~rtherm!a:byTRHis deb~tab!e [2:~:]~ar~!~yant characteristicof T ~ H treatmentmay be the reversalof hypo~hermia~h!¢h haSbeen demonstrated in pharmac01o#ca!!y~nduced hy~thermia [1:~]r~,S0m~i ~ t ~ g a t 0 r s have demonstrated a beEm~fiCrialeffcctofhypothermia on:the rbiOCher+i~O.~Changes
301
!' ii!
J
TRH 4~
~o~ Saline Control
3-
Values :~ $E
Hour8 Post L[gat|on Fig. 1. Neurological s~'~e of treated and control group ischemie gerbils as indicated by the stroke inde×. The hislier:the strol<¢ index, the worse the condition.
of cerebr~ . . ischemia, . . However, other complications have made this treat1~tent rnoda]ity~ ~ntroversml [ 2 6 L H ~ t ~ r m ! a ~s a known ~equela~ to Cerebral ~schernia in ~he :gerb~:s~r6ke ~0deL Drugs whiehdeplete Catechol~nine:~ or block theh: receptors retumthe: animal :to normoth~mia~ .repol~ed!y with no change i~ r~qorb~ity or
302
mortality [24]. The profoundly adverse effect of TRH on gerbil sm~iv~ in the st~'oke model is ~,,nlikely to be ~ . ~ e d with thermoregu|ation. in vitro experiments have demonsgratedthe p a r ~ t a S _ ¢ m ~ s t ~ u ! a t ~ release of biogenic ambles ~nd: of TRH inca wide v ~ s?imulated release of d o p ~ n e [ 2 ] ' . : l n vivo s y a ~ c : ~ H iSd~,inistration i n i O g f ~ t has been able to alter biogenic amine metabolism only after chronic d/~Sing I l l ~. Neuro:ransmitters are implicated in the t~thophysi01ogY;0faroke, butevidenee f o r TRH involvement via this mechanism is hcking.:An i~uCed decrease:~ ~ r e b r a l glucose utilization may result from acute TRH treatment without altering neuro~ransmitter turnover [25]. The opposite effect of TRH resultedif tl~e rats had been treated with pentobarbit~. Thus, TRH alters metabolism in a complex fashion. The recent immunohistochemicai demonstration o f TRH in the same medullary neurons with serotonh and substance P by Johansson and co-workers [16] prompted their citing the known physiologicalrelationship of rierves in exocrine glands, some of which contain both acetylcholine and vasoactive intestinal ~ p t i d e
oflb¢ifini:!re~ofis~p!Usi:a~
(VIP) and :~thers which contain norepinep~rin¢ and avian pancreatic p~lypeptide (APP). Both acetylcholine and VIP potentiated the secretion of the gland via stimulating their respective receptors to increase blood flow: :In con~raS', the coexisting norepinephrinc-APP nerve produced vasoconstriction, probably ::by an. APP blockade of ~he V~P response together with direct adrenergic receptor stimulation. The potential complexity of central peptide-transmitter interactions is evident. The inter~:tion of TRH on the ischemic brain with energy metabolism, neurotransmitter syster~as and blood flow is yet to be established in comparable detail. Because of its many crgotropic properties in healthy organisms, exogenous TRH has been proposed to ~upplement post-anesthesia recovery of consciousness and respiration and to the diagnosis of brain death [22L The deleterious effect ~in this present study of exogenous T R H in the gerbil stroke model should provoke considerable caution on its use in therapy of pathological or compromised situations until further elaboration of TRH's role Can be undertaken [18]. 1 Agarwai, R.A., Rastogi, R.B. and Singhal, R.L., Enhancemem of locomotor Activity and
catechoiamineand 5-hyflroxytrypmminemetabolismby thyrotro6inreleasing~bo~mone,Neuroendocrinology,23 (197"/)236-247. 2 Bennett, G.W., M~rsden, C.A., Sharp, T. and Stolz, J.F., Concomitant determinationof endogenous releaseof dopamine, noradrenaline,5-hydroxytry~t~mineand thyrolropin releasinghormone (T'RH)from rat brain slices~nd ~ynaptos~mes.In C,L PycockandP.V. T~berncr(rgl~Ji,Central NeurotransmitterTurnover, UniversityPark Press, New York, 19~1, pp. 1~3-189. 3 Berry, K., Wi~niewski,H.M., Svar~-P,ein, Lo a~d Baez, S., On the relationshipof brain vasculature to productionof neurologicaldeficitand morpholo~calchanges£ollowingacute unilateralcommon carotid artery l!gation in g~:~b~, L ncuroL Sci,~ 2~ (1975)75~92: ~:r:I / " / i "r L r 4 Brees¢, G.R:) Mueller, R.A~. Ma~|~aan, R.B. •~a~id]['rye; G.D~:~in T[~e :R~[~ bf Pei~id~s:Sr/d ~n~[no 5 Dodson, R.F., Chu, L.W.-F., Wel~.h,K.M,A: and Aeh~r, V.S., .AcUte:ti~s~.~:resi)Ohse: tO:cerebral ischemia in ~he gerbil, J. neurol. Sci., 33 {1977) 161--170.
303 6 Faden, A~!.,Jacobs, T,P. and HoladaY, J.W., Opiate antagonist improve:~ neurologic recovery after spinaJ injury, Science, 211 (1981) 493-494. 7 Faden, A.I., Jacobs, T.P. and Holaday, J.W., Thyrolropin-relc~sing hormone improves neurol~ic recovery afro.t-spinal trauma.in cats, N. Engl. J. Me~., 305 (1981) i063-1067. 8 Faden;A~L~:ja-cobs,: T~Pi,!MougeY;Eo:and Holsdf~y,J.W., End0rph)ns in experimental spinal injury:i therapeufieeffect ~f:naloX0ne, Ann.)Neur01.i 10(1981)326-33,L 9 Halsey, .LH., Ganji i s.iErdmsnn~ w. andMardis,H., Studies in cerebral isChemia, Microvasc. Res.,~ 13 (1977),363-/370.. I0 Hannan~fC.J., NewgerbiI stroke model, So¢. Neur0sci. Abstr., 6 (1980) 827. 1: Holaday;~J.W:~Tseng, L.-F., L0h ~,H.H. and Li, C.H., Thyrotropin releasing hormone antagonizes B-endorphin hypothe~imia and catalepsy, Life Sci,, 22 (!978) 1537-1543. 12 HosObuch!, Y., Baskin, D:S. and Woo, S.K., Reversal of i~duced ischemic neuroiogic deficit in gerbils by the opiate antagonist nalo×one, Science, 2!5 (1981) 71-79. 13 Ire, U., Ohno, K., Suganuma, Y., Suzuki, K. and Inaba, Y., Effect of steroid on isehemic brain edema. Analysis of cytotoxic and vasogenic edema occurring during ischemia and after restoration o f blood flow, Stroke, 11 (1980) 166-172. 14 Ire, U., Spatz, M., Walker, J.T. and Klatzo, I., E×perimemal cerebral ischemia in Mongolian gerbils I. Light microscopic observations, Acta neuropath., 32 (1975) 209-223. 15 Jarrott, D.M. and Dovaer, F.R., A gerbil model of cerebral ischemia suitable for drug evaluation, Stroke, 11 (1980) 203-209. 16 Johansson, O., H~kfelt, T., Pernow, B., Jeffco~te, S.L., White, N., Steinbush, H.W.M., Verhofstad, A.A.J., Emson, P.C. and Spindel, E., Immunohistochemical support for three putative transmitters in one neuron: co-existence of 5-hydroxytryptamine, substance P- and thyrotropin releasing hormone-like immunoreactivity in medullar~ neurons projec;ing to the :~pinal cord, Neuroscience, 6 (1981) 1857-1881. 17 Levine, S~ and Payan, H., Effects of ischemia and other procedures on the brain and retina of ~he gerbil (MerionesunguiculatusL E×p. Neurol., 16 (1966) 255-262. 18 Maeda, K. and Tanimoto, g., Epileptic seizures induced by thyrotrop~r~ releasing hormone, Lancet, ii (1981) 1058-1059. 19 McGraw, C.P., Experiment~ cerebral i~fa~ction effectsof pentobarbit~ ~in Mongolian gerbils,Arch. Neurol., 34 (1977) 334-336. 20 McGraw, C.P., Crowell, G.I:. and Hov~r~LG., Effect of aminophyllin,,,on cerebral infarction in the Mongolian gerbil, Stroke, 9 (1~78) 477o~479. 21 McGraw, ~C.P., P~hayan, A.G. and Weldel, O.T., Cerebral infarct:or. ~n the Mongolian gerbil exacerbated by phenoxybcnzaafin¢ treatmem, Stroke, 7 (1956) 485-48'3. 22 Metcalf, G. and Dettmar, P.W., Is thyrotro~in releasing hormone a:~ endogenous ergotropic substance in the brain? Lancet, i (tggl) 586-589. 23 Morley, LE., Extrahypothalamic thyrotropin rele~,~:~g hormone (TRH~ - i~s distribution and functions, Life Sci,, 25 (1979} 1539-1550. 24 Moskowi*.z, M.A., Meyer, E., Wurtman, R.J., LavTae, M.H. and Zcrvas, N.T., Attenuation by eateehol~mine ~ttagonists of the hypothermia that fo~lows cerebral infarction ill gerbils, Life Sci., 17 (1975) 597-602. 25 Nagai, Y., Nanimi, S., Nagawa, Y., Sakurad~, O , Ueno, H. and lshi~, ~g., Effect of thyrotropit~ releasing hormone (TRH) on local cerebral glucose utilization by the autoradk'~raphi, 2.dcoxy[t4C]glucos¢ method, in conscio~ ~md l:mntobm'bitalized rats, J. Nem'c~:hem., 35 (!980~ 963-971. 26 ,~lmml, W.R. and Spetzler, R.F., Ther~eutic~ for f~>calce~ebra! ~.schem~.) Neurosurgery, L (1980) 446-452~ 27 S~ffurth, J~S., G~bberd, M.C. and Ng Tang Fui, S.., Arterial e.~nboli~m ~n ~hyro~;o×ico~iswith atrial fibrillation, Brit. mad. J., 2 (1977) 688-690. 7
~
299
Elsevier Scientific Publishers !re]~a~ Ltd.
CHAR~:(:J~ -:HAHNAN, fir.-and A N G E L R . GAKCIfA§': " C e n t e r , Fort G o r d o n , GA-:JOgOf tU, S ~ A J - '
"
"
"
-f
The gerbilmodelfor stroke, using permanent unilateral carotid artery occlusion and restriction of the contralateral artery, was used to assess exogenous thyrotr,~pin-relea~ng hormone (TRH~ ]0 mg/kg, i.p.) effect on: cerebral ischemia: TRH innncdiately post~occlusion, compared to saline controh, significantly increased m o ~ t y (P: = 0.ff25). This was supported by worsening refle.~ted in the stroke index and time to death, Thyrotropin (0. i IU, i.p,) in the same model was without effect. These surprising results were unexpected due to the beneficial response to ~he pharmacologicaily related naloxone.
Thegerbil. has been used extensively as a model for studying the pathophysiology of cerebral infarction [5,9, 14] ever since the discovery by Levine and Payan [17] of this animal's unique susceptibility to cerebral ischemia. The gerbil lacks an artery communicating the major anterior blood supply from the internal carotid artery with the posterior basilar arterial blood supply [3]° This allows a relatively simple common carotid artery occlusion to produce closed head cerebral ischemi~ for experimental study. Using this model, a number of investigators have examined the value of: e x ~ m e n m t drug therapies to improve the morbidity or mortality consequent to the induced isehemia [13, 15, 191.Some agents such as phenoxybenzami~e [21], atropine, thiosernicarbazide, pheny*oin, theophylline [15] and an~nophylline [20] have proven to be dele~:erious to the recovery or to the amelioration of neurolo#c damage. Thyrotropin-releasing hormone (TRH) was chosen for evalu:~tion in the gerbil stroke model because of its beneficial effects in a s#nal trauma model in cats [7]. The rationale also included the improvement of neurologic deficits in~ the rgerbil stroke model by the pharmacolo#cally related compound, naloxone * In conducting the research described in this report, the investigators adhered ~.othe 'Guide for the Care and Use of Laboratory Animals', as promulgated by the Commfftee on .~,evision of the Guide for La~ra~ory. Animal FaCilities and C~/re, of the Institute of Laboratory Animal F~esourees, National :The:~piiiions or asse;;fions contained h~,~eirfare the private views of the authors and ~re rtot to be constrtted as 0ff'~:ial~of:as ~:eflecdng the views of th~ Department of Army or Department of Defense° 0304-3940/82/0(KAk-00f~/$ 02.75 © 1982 Elsevier $cie~~tific Publishers Ireland Ltd.
34)0 ,
.
•
++
.
+':
+r
¸ /'+,
,
[12]. Naloxone-induccd improvement in. the c~: s p ~ tramim mode!i [6+ 8] +hmd originally led to ,the tri~ of TRH i n that model |7]+,TRH hm+a+m+i~y0feff~+ts when administeredsystemically besidesthe release+of+th~ot~op~nC~H)[4]L, T h ~
one possesses. It s ~ m e d logicalto extendthe ¢~m~natio~ oftl~¢,~fiCi~l~effe~t repo ted to be produc+d by TRH therapy, It was very ~ Z i s ~ i t o , fi~d z ~ , ~ o u S i , ~ o ~ oF~m0rbi~ty~i~d~I mortality in TRH-tremed exper~ental, animMs 'ilt~t h e i ~ . ~ nti ~udy/:i ~:~:~:/+Y:I.~:}i~!Yl;:!~:= Thirty Meriones ungu~culatus, Turn. (MO .!~., .mah~talned ona reversedJ2~hl!gh~ t, 12-h dark cycle, had their left commoncarotid artery occluded.,and right common carotid restricted under ketamine anesthesia (50 mg/kg) between 08.30and 10.30 h [10]. Immediately after suturing the: exnployed midline incision, either TRH:I~10 mg/kg, i.p. in 2 mg/ml sterile saline+ Sigma Chemicai) or an equal volumeofsal~+Me was injected alternately in occludedgerb~lS. Animals were ~ami~ia~:r07,~:~!6~00 ~'ld 23.00rh andwere evaluated ngurolOgically a s describ~ by MCGra~ [!9]~:~t672 h post ligation. At the end of one week, the TRH group had 12 (80~/0) mortalities, whereas the saline control group had 6 (40¢/0). The difference is significant by the chi-square test (P = 0.025). The median survival time forthe control group was greater than 72 h and for the TRH group was 31 h. :['he neu.~¢logical evaluation is summarized in Fig. 1 as the mean stroke index at each 8 h interval. The highe~ the Stroke, index, the worse the neurological condition of the animal. A measure of time-to-death (Lee-Desu statistic, P = 0.0728)and comparison of the stroke indices at: the 9 observation times (Wald-Wolfowitz Runs Tests, P < Oo02), also indicated that the t~,~o groups were different (these non-parametric computer analy~es are pastor ther SPSS Batch System softwareL Oneweck after oc¢lusion,allsUr*d~ing~ animals ~ere fixed by pcrfusion with Carsons' buffered forma!in and,: processed~ for fight microscopy, One of the 3 survivors :in the TRH group and 2 of~the 9su~ors~ir~ the control group had histologicallydemonstrat¢fl cetebraI~nfarctions.: ' Because of the unexpectedly devastating effect of ~RH on thei~hemicanimals~ the possibility of idiosyncratic reaction was conside~red. TR]~ in cquivalent~dos~: was injected into normal gerbils withoutunusualeffec~, DeSpite the limited evidence for a pathological effect o~' thyrotropin (TSH)in cerebral ~schemia [27], a~dose of 0.1 international unit of TSH was injected intrapcritoneally into each of a group of 15 occluded gerbils with 15 occluded saline controls. Mortality figures did not indicate a~y effecL
Although the production of hyi~rtherm!a:byTRHis deb~tab!e [2:~:]~ar~!~yant characteristicof T ~ H treatmentmay be the reversalof hypo~hermia~h!¢h haSbeen demonstrated in pharmac01o#ca!!y~nduced hy~thermia [1:~]r~,S0m~i ~ t ~ g a t 0 r s have demonstrated a beEm~fiCrialeffcctofhypothermia on:the rbiOCher+i~O.~Changes
301
!' ii!
J
TRH 4~
~o~ Saline Control
3-
Values :~ $E
Hour8 Post L[gat|on Fig. 1. Neurological s~'~e of treated and control group ischemie gerbils as indicated by the stroke inde×. The hislier:the strol<¢ index, the worse the condition.
of cerebr~ . . ischemia, . . However, other complications have made this treat1~tent rnoda]ity~ ~ntroversml [ 2 6 L H ~ t ~ r m ! a ~s a known ~equela~ to Cerebral ~schernia in ~he :gerb~:s~r6ke ~0deL Drugs whiehdeplete Catechol~nine:~ or block theh: receptors retumthe: animal :to normoth~mia~ .repol~ed!y with no change i~ r~qorb~ity or
302
mortality [24]. The profoundly adverse effect of TRH on gerbil sm~iv~ in the st~'oke model is ~,,nlikely to be ~ . ~ e d with thermoregu|ation. in vitro experiments have demonsgratedthe p a r ~ t a S _ ¢ m ~ s t ~ u ! a t ~ release of biogenic ambles ~nd: of TRH inca wide v ~ s?imulated release of d o p ~ n e [ 2 ] ' . : l n vivo s y a ~ c : ~ H iSd~,inistration i n i O g f ~ t has been able to alter biogenic amine metabolism only after chronic d/~Sing I l l ~. Neuro:ransmitters are implicated in the t~thophysi01ogY;0faroke, butevidenee f o r TRH involvement via this mechanism is hcking.:An i~uCed decrease:~ ~ r e b r a l glucose utilization may result from acute TRH treatment without altering neuro~ransmitter turnover [25]. The opposite effect of TRH resultedif tl~e rats had been treated with pentobarbit~. Thus, TRH alters metabolism in a complex fashion. The recent immunohistochemicai demonstration o f TRH in the same medullary neurons with serotonh and substance P by Johansson and co-workers [16] prompted their citing the known physiologicalrelationship of rierves in exocrine glands, some of which contain both acetylcholine and vasoactive intestinal ~ p t i d e
oflb¢ifini:!re~ofis~p!Usi:a~
(VIP) and :~thers which contain norepinep~rin¢ and avian pancreatic p~lypeptide (APP). Both acetylcholine and VIP potentiated the secretion of the gland via stimulating their respective receptors to increase blood flow: :In con~raS', the coexisting norepinephrinc-APP nerve produced vasoconstriction, probably ::by an. APP blockade of ~he V~P response together with direct adrenergic receptor stimulation. The potential complexity of central peptide-transmitter interactions is evident. The inter~:tion of TRH on the ischemic brain with energy metabolism, neurotransmitter syster~as and blood flow is yet to be established in comparable detail. Because of its many crgotropic properties in healthy organisms, exogenous TRH has been proposed to ~upplement post-anesthesia recovery of consciousness and respiration and to the diagnosis of brain death [22L The deleterious effect ~in this present study of exogenous T R H in the gerbil stroke model should provoke considerable caution on its use in therapy of pathological or compromised situations until further elaboration of TRH's role Can be undertaken [18]. 1 Agarwai, R.A., Rastogi, R.B. and Singhal, R.L., Enhancemem of locomotor Activity and
catechoiamineand 5-hyflroxytrypmminemetabolismby thyrotro6inreleasing~bo~mone,Neuroendocrinology,23 (197"/)236-247. 2 Bennett, G.W., M~rsden, C.A., Sharp, T. and Stolz, J.F., Concomitant determinationof endogenous releaseof dopamine, noradrenaline,5-hydroxytry~t~mineand thyrolropin releasinghormone (T'RH)from rat brain slices~nd ~ynaptos~mes.In C,L PycockandP.V. T~berncr(rgl~Ji,Central NeurotransmitterTurnover, UniversityPark Press, New York, 19~1, pp. 1~3-189. 3 Berry, K., Wi~niewski,H.M., Svar~-P,ein, Lo a~d Baez, S., On the relationshipof brain vasculature to productionof neurologicaldeficitand morpholo~calchanges£ollowingacute unilateralcommon carotid artery l!gation in g~:~b~, L ncuroL Sci,~ 2~ (1975)75~92: ~:r:I / " / i "r L r 4 Brees¢, G.R:) Mueller, R.A~. Ma~|~aan, R.B. •~a~id]['rye; G.D~:~in T[~e :R~[~ bf Pei~id~s:Sr/d ~n~[no 5 Dodson, R.F., Chu, L.W.-F., Wel~.h,K.M,A: and Aeh~r, V.S., .AcUte:ti~s~.~:resi)Ohse: tO:cerebral ischemia in ~he gerbil, J. neurol. Sci., 33 {1977) 161--170.
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