Cerebellum site and mode of antivertigo action of thiethylperazin

Guth, P. S.

English

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* b  ' .  
In the original grant application the proposed research objectives were 
divided into three general areas: 
1. Determination of areas  of localization of thiethylperazine 
in mammalian cerebellum and associated areas ,  
2. 
3. 
Drug binding to the subcellular elements of cerebellar areas.  
Site of action of thiethylperazine in humans and animals. 
The results have been The f i rs t  objective was realized completely. 
published and reprints accompany this report. Briefly, the results illustrate 
that the anti-emetic phenothiazine, thiethylperazine, has a spectrum of 
localization within dog brain quite different from those of tranquilizer 
phenothiazine, chlorpromazine and pro c hlo r pe r azine. 
localizes primarily in vermis, paraflocculus, cerebellar cortex and fastigial 
nucleus of the cerebellum and restiform body and area of vestibular nuclei. 
This pattern of localization delineates, meaningfully o r  not, a cerebello- 
vestibular nervous pathway. 
to follow attempting to correlate sites of localization with sites of action. 
The overall plan to correlate these sites was to produce lesions in 
T hi e thylp e r a zine 
This study laid the groundwork for the studies 
the a r e a s  of drug concentration and to determine whether the drug retained 
i t s  anti-nystagmic and anti-emetic actions. For  these studies cats, dogs 
and humans were employed. 
means available for  quantitating drug effects was by rating (0-4t) nystagmus and 
body attitude before and after drug and before and after surgery. 
extremely inaccurate and clumsy. However, these early efforts stimulated 
the development of methods for electronic recording of nystagmus. 
human studies were included six patients with cerebellar degeneration a s  
well a s  a normal population and a population of patients with vestibular problems. 
Nystagmus and subjective dizziness was produced in the normals and patients 
with cerebellar lesions before and after drug and placebo administration. 
Duration of nystagmus and subjective dizziness was recorded before and after 
At the time that the cats were studied, the best 
This proved 
In the 
drug ayld placebo. The norm21 n a f i p n t s  a s  well a s  those with vestibular problems 
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responded very well to thiethylperazine with a reduction in duration and 
severity of dizziness and nystagmus. 
on the other hand received significaritly much less  protection (4 /6 showing 
no protection). 
The cerebellar degeneration patients 
In the dogs a s  well, cerebellectomy severely attenuated the anti-nystagmic 
action of thiethylperazine. 
A colony of swing-sickness susceptible dogs was selected and the 
protective effect of thiethylperazine noted. 
discrete a reas  of these animals cerebelli and associated a reas  were made, but 
primarily because of variation in animal head size and shape the lesions could 
not be predictably placed. 
Attempts at producing lesions in 
After 18 months of trying this project was abandoned. 
The subcellular distribution problem was like-wise abandoned when it was 
realized that redistribution of drug among the various subcellular fractions 
could easily occur during homogenization and centrifugation. 
means to  control for redistribution was a t  hand. 
No apparent 
In brief summary, the successful research demonstrated: 
1. 
2. 
3. 
4. 
That thiethylperazine localizes differently from tranquilizer 
phenothiazines. 
That the major brain a rea  of highest concentration in  dog 
and rabbit is the cerebellum and areas  associated with 
vestibular function. 
That thiethylperazine exerts i ts  antinystagmic action in dogs 
and humans, antivertigo action in humans and antiswing- 
sickness actions in dogs. 
That the cerebellum needs to be intact fo r  thiethylperazine 
to produce i ts  anti-nystagmic action. 
Thus an approach to correlating sites of action and localization has been 
made which has been partially successful. 
a r e  reprints of two publications and a senior medical thesis 
resulting from this work. 
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Investigation into the site and mode of antivertigo action of a new phenothiazine derivative Final report

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