A possible neurochemical mechanism for brain and nerve damage associated with chronic alcoholism – documents que es la anoxia

771”S – S;~ptember I YH2

Pramsin-like effect could explain the

Decreases in tierial mood pressure it

Causes; this interpretation is hard to recon.

Tile with the preliminary observations that

Ketanserin. In doses which lower arterial

Blood pressure in man, does not shift the

Pressor re:qonse curve to phenylephrine to

The right (schalekamp. Personal communk

Cation).

The thesis that 5-hydroxytryptamine

May play a role in established hypertension

Is based on the following observations: (I)

In several animal models of chronic hyper-

Ter.Sion there is a specific increase in the

Responsiveness of the blood vessel wall


To the vasoconstrictor properties of

5-llydroxytryptamine and a delayed

Tachyphylaxis to the monoamine; (2) the

que es la anoxia

Abdity to clear S-hydroxytryptamine from

The blood in the lungs is reduced in the spon-

Tzuleously hypertensive rat. In platelets

From hypertensive patients, the uptake of

5llydroxytryptamine is reduced, but the

Aggregability increased; and (3) an SY-

Serotonergic antagonist, devoid of agonistic

Pr3)perties, lowers arterial blood pressure in

H) pertensive humans and animals.

373

Acknowledgement ~i’MI,~,~thehis

Is proposed which ultimately bears close

Analogy with the mechanisms of estah

Lish;d cellular toxins. It depends on the

Formation of the reactive aldrhydic species

From etoh and , cvldencc for rhe

Occurrence of T1Q.S was imuted. But it nou

Is certain that the! Are in 1,;) o pnniucr?. \)I

EtOH metab +m.Que es la anoxia sub~ti~nd quanriiie3 c,t

Omerh!,lated ‘TIQ derivati\c’ substrate

Fuss no1 been excluded), microsomal

Enzymes. Or even activated oxygen or hyd.

Roxyf radicals. Oxidative decarboxylation

Of f-carboxyct1qs has already been shown

To occur” rn aqueous bicarbonate and in

Fungal enzyme systems (fig. 2). Thus. It

Appears that there is some literature suppon

For the notion that the tiqs produced in

Alcohol abuse could undergo oxidative

Conversions.

Tfae key feature of this hypotftesis is tfte

Apparent in~~~~ivernent of a reactive ‘oxid

Ized tfq’ in alcoholic neurotoxi~city. Based

On tfte falck-hiffarp ex,periments with

Formaldehyde-related diqs, and experf-

Ments in our laboratory with the anafogous

Acetafdehyde derivatives.Que es la anoxia it appears that

Most catecftofic diqs (and fsossibfy fqs

And N-oxides) exist almost exclusively as

Quinoidal tautumers at phys~~:!Ogicaf phs

(fig. 3). What is apparent in fig. 3 is the

Striking electronic and strueturaf similarity

Betuzen these quinoidamine tautomers and

The ~~xidized ele~tr~hifi~ quin~;ne 01.

Utydroxy-dopamine (OH-DA). A potent

Pharmacological ncurotoxin. The action of

OH-DA is dependent initially on uprakc

Into CA neurons and subsequently on rapid

Oxidat~~~n to at least two active species. Its

Electron-deficient quinotte and hydrogen

Peroxide. If the quinoidamine tautomers of

The dfqs. IQs, or their N-oxides share even

A degree ofthe highly electrophilic nature of

B-OH-DA yuinonc. The oxidized condense

que es la anoxia

Non products ought to hecapable of produc-

Ing neuronaf damage via covalent attach

Mcnt (arrows. Fig. 3) 15 membrane nuc-

Leopftifes. ~#iculariy sulfhydryfs. In a

Manner similar to -OH-DA. Fm~~antly.

Theelectrophilicity of such tautomers would

Be predicted to be enhanced if the nitrogen

Were oxidized. As suggested, or if the

R-group were efe~~~wi?HdrawinF. Tftis

Fatter situation may be the case wften R is a

Benzyl group in the original TIQ (such as

Tetrahydropapaveroline or its I-carboxyf

Analogs). Since an afpfta-kefo function

Appears likely to form ~ntan~uslyi’ dur-

Ing DIQ production (DIQ if. Fig. 2).

While general pharmacofogicaf profiles

Of various diqs and iqs have been pub.

Fished. Little is known about their long-term

que es la anoxia

Cellular effects. ~efimin~ studins in this

Laboratory, assisted by dr S. Lorens and P.

Pate]. Indicate that hisropatholcgy and

Biogenic amine depletion is evident in rats 2

Weeks after termination of several intra-

Striatal inj~tions of the DIQ II t zig. 2)

Related to ‘tw, this pmvocaiive iinding is

Being pursued. Additionally. There is a

Report mentioned above. Of a ‘OH-DA-

Like’ effect of an ~ren~li~de~v~ TIQ

Which could involve. In this case. An iscr

Quinoline derived from loxidation or

3,qdehydration or both.

Absolute identity of action between the

Proposed diqs for derived quinoids) and

OH-DA is not a ~~arnen~f requirement

Of this hyfxnhesis. Tfte oxidized condensa-

Tion products need not have the extensive

que es la anoxia

Efectrophfficity and suffhydryf-biding

Capability of (oxidized) 60KDA. Which

Is administered usuaffy as a large singie

Dose. Since the isoquinofines are believed to

6-HO-DA

IX0 kilji~amtne 1

B-HO-DA OUINONE

Form on a trace. Chronic basis river ycarb

And perhaps decades. Secondly. Restriction

Of the neuronal damage to 4CA neurons. As

With OH-DA, is not obligato~ for

Endogenously-praised ‘alkaloids’. Since

The cyclic CA products couid and do

Interact with various neuronal systems. For

Example, while tiqs and DIQP are taken

Up by CA neurons, in our laboratory we

Have observed that a potential DIQ precur-

Sor (a sar~xyiated TIQ) has greater and

Eariier effects on rat brain levels of seroto

Nin than of cas. Indicating significant

que es la anoxia

Involvement with serotonergic systems.

Also. Enzymatic O-methylation of catechol

TlQs and diqs. A route expected to block

The proposed todc mechanism if it involved

The 6hydroxyi group (by analogy to the

Meta-hydroxyl of cate~~~amines). Might

Not be a competing factor. Qur results indi-

Cate that. Contrary IO expectations, it is the

7-hydroxyl of various tlqs which is pre-

Dominantly methylated in rat brain. Furth

Ermore. Catecholic dlqs do not even

Appear to be substrates for ~methylati~)n~~

VivoJJ. Based on this info~tion. The for-

Mation and action of the quinoidal tautom-

Ers should not be prevented by catechol-

D-methyltransferase.

In a number of studies, alcoholic damage

Has been likened to or actually resembles

que es la anoxia

Premature aging of the brairp. It is

Notewo~y that beta-carbolines. Eondens;

Tion products of indoleamines, may hr

Membrane cross-linking agents in the nor-

Mal aging of human lens tissues”. TIQ oxi-

D?:ion products could be conceived of as

Analogous agents in an alcohol-induced

Aging process, via the covalent mechanisms

Suggested. The co~~~~io~ox~dation

M~hanisms may also explnin the known

Individual variations in brain dama@ and

Psychological deficits among chronic

Alcoholics. That is. Subsequenr lo a general

Non-enzymatic condensation (TIQ forma

Lion) regulated by precursor availability,

The catalysed pr~uctiort of oxidized iso.

Quincclines might be a proccs\ uith signtfi-

Cant genetic differences betueen alcoholic

que es la anoxia

Individuals.

The TJQ/dlq/IQ rn~h~~srns outfined

Iould he occurring in other forms of

Rclcohol-induced tissue pathology as II 41.

Researchers have suggested that acetab

Dehyde (ach) may have a role in alcohohc

Liver injury. In view of the evidence for

Bepatic necrosis due to an ach-derived

TJQ in rats’“. It is possible that oxidized

TIQ species may be involved. AcH has

Been impheated in atcohohc cardiac dr.S

Ease; dfqs or 1qs derived from heart C.A\

And aldehydes or alpha-keto-acids could TV

Addittonal long-term pathological agent5 in

1 his peripheral organ.

In summary, in view of the avackcble ev i-

Dence, a discrete molecular n~e~h~tni~nl

,which could underlie aspects of aicohot

Induced brain and nerve damage is discus

que es la anoxia

3rd here. It is dependent on the intermtd-

Racy of ach (and possibly other carbony

Ntetabolites) and on the oxidative formation

Of minute 3mounts of neuronal dfqs.

Pi-oxides and their ~~t~nt~~~y ele~tr~~phi~t~

Tautomers which could serve as covalent

Btndinp agents over years of alcohol abuse.

Of course, this dots not obviate other

Nlcchanisms which might sontribute. Such

As direct ach and eroh membrane intrrac-

Tions. Chronic inhibition of essential brain

Trar;sport and protein synthesis”.

Ir~rnunog~ni~ factorp. Or even the rela

Tiveiy early suggestion of blood ‘sludp

Ing”Y. Efforts are underway in our labor-

Tory to test the validity of this ovemll chemi

Cal hypothesis in studies on TIQ ouidarivr

Conversions and effczts.Que es la anoxia and hopefully. The

Idea will provoke investi~atil~ns in other

La~~mtor~es.

The author acknowledges the helpful

Discussions with drs william nijm. Stan-

Ley lorens, J. Hannrgan and T. Origitano at

Loycla university, ur murray hamilton at

Sc~thr\c\~ f~untkcttc~n ior ke\carzh. San

€˜~ntc~r~ic~. Deba cyhara of chrc~go and dr

Wattcr os~vrald at the r.€˜nivcr

771”S – S;~ptember I YH2

Pramsin-like effect could explain the

Decreases in tierial mood pressure it

Causes; this interpretation is hard to recon.

Tile with the preliminary observations that

Ketanserin. In doses which lower arterial

Blood pressure in man, does not shift the

Pressor re:qonse curve to phenylephrine to

The right (schalekamp. Personal communk

que es la anoxia

Cation).

The thesis that 5-hydroxytryptamine

May play a role in established hypertension

Is based on the following observations: (I)

In several animal models of chronic hyper-

Ter.Sion there is a specific increase in the

Responsiveness of the blood vessel wall

To the vasoconstrictor properties of

5-llydroxytryptamine and a delayed

Tachyphylaxis to the monoamine; (2) the

Abdity to clear S-hydroxytryptamine from

The blood in the lungs is reduced in the spon-

Tzuleously hypertensive rat. In platelets

From hypertensive patients, the uptake of

5llydroxytryptamine is reduced, but the

Aggregability increased; and (3) an SY-

Serotonergic antagonist, devoid of agonistic

Pr3)perties, lowers arterial blood pressure in

H) pertensive humans and animals.Que es la anoxia

373

Acknowledgement ~i’MI,~,~thehis

Is proposed which ultimately bears close

Analogy with the mechanisms of estah

Lish;d cellular toxins. It depends on the

Formation of the reactive aldrhydic species

From etoh and , cvldencc for rhe

Occurrence of T1Q.S was imuted. But it nou

Is certain that the! Are in 1,;) o pnniucr?. \)I

EtOH metab +m. Sub~ti~nd quanriiie3 c,t

Omerh!,lated ‘TIQ derivati\c’ substrate

Fuss no1 been excluded), microsomal

Enzymes. Or even activated oxygen or hyd.

Roxyf radicals. Oxidative decarboxylation

Of f-carboxyct1qs has already been shown

To occur” rn aqueous bicarbonate and in

Fungal enzyme systems (fig. 2). Thus. It

Appears that there is some literature suppon

For the notion that the tiqs produced in

que es la anoxia

Alcohol abuse could undergo oxidative

Conversions.

Tfae key feature of this hypotftesis is tfte

Apparent in~~~~ivernent of a reactive ‘oxid

Ized tfq’ in alcoholic neurotoxi~city. Based

On tfte falck-hiffarp ex,periments with

Formaldehyde-related diqs, and experf-

Ments in our laboratory with the anafogous

Acetafdehyde derivatives. It appears that

Most catecftofic diqs (and fsossibfy fqs

And N-oxides) exist almost exclusively as

Quinoidal tautumers at phys~~:!Ogicaf phs

(fig. 3). What is apparent in fig. 3 is the

Striking electronic and strueturaf similarity

Betuzen these quinoidamine tautomers and

The ~~xidized ele~tr~hifi~ quin~;ne 01.

Utydroxy-dopamine (OH-DA). A potent

Pharmacological ncurotoxin. The action of

que es la anoxia

OH-DA is dependent initially on uprakc

Into CA neurons and subsequently on rapid

Oxidat~~~n to at least two active species. Its

Electron-deficient quinotte and hydrogen

Peroxide. If the quinoidamine tautomers of

The dfqs. IQs, or their N-oxides share even

A degree ofthe highly electrophilic nature of

B-OH-DA yuinonc. The oxidized condense

Non products ought to hecapable of produc-

Ing neuronaf damage via covalent attach

Mcnt (arrows. Fig. 3) 15 membrane nuc-

Leopftifes. ~#iculariy sulfhydryfs. In a

Manner similar to -OH-DA. Fm~~antly.

Theelectrophilicity of such tautomers would

Be predicted to be enhanced if the nitrogen

Were oxidized. As suggested, or if the

R-group were efe~~~wi?HdrawinF. Tftis

Fatter situation may be the case wften R is a

que es la anoxia

Benzyl group in the original TIQ (such as

Tetrahydropapaveroline or its I-carboxyf

Analogs). Since an afpfta-kefo function

Appears likely to form ~ntan~uslyi’ dur-

Ing DIQ production (DIQ if. Fig. 2).

While general pharmacofogicaf profiles

Of various diqs and iqs have been pub.

Fished. Little is known about their long-term

Cellular effects. ~efimin~ studins in this

Laboratory, assisted by dr S. Lorens and P.

Pate]. Indicate that hisropatholcgy and

Biogenic amine depletion is evident in rats 2

Weeks after termination of several intra-

Striatal inj~tions of the DIQ II t zig. 2)

Related to ‘tw, this pmvocaiive iinding is

Being pursued. Additionally. There is a

Report mentioned above. Of a ‘OH-DA-

Like’ effect of an ~ren~li~de~v~ TIQ

que es la anoxia

Which could involve. In this case. An iscr

Quinoline derived from loxidation or

3,qdehydration or both.

Absolute identity of action between the

Proposed diqs for derived quinoids) and

OH-DA is not a ~~arnen~f requirement

Of this hyfxnhesis. Tfte oxidized condensa-

Tion products need not have the extensive

Efectrophfficity and suffhydryf-biding

Capability of (oxidized) 60KDA. Which

Is administered usuaffy as a large singie

Dose. Since the isoquinofines are believed to

6-HO-DA

IX0 kilji~amtne 1

B-HO-DA OUINONE

Form on a trace. Chronic basis river ycarb

And perhaps decades. Secondly. Restriction

Of the neuronal damage to 4CA neurons. As

With OH-DA, is not obligato~ for

Endogenously-praised ‘alkaloids’. Since

que es la anoxia

The cyclic CA products couid and do

Interact with various neuronal systems. For

Example, while tiqs and DIQP are taken

Up by CA neurons, in our laboratory we

Have observed that a potential DIQ precur-

Sor (a sar~xyiated TIQ) has greater and

Eariier effects on rat brain levels of seroto

Nin than of cas. Indicating significant

Involvement with serotonergic systems.

Also. Enzymatic O-methylation of catechol

TlQs and diqs. A route expected to block

The proposed todc mechanism if it involved

The 6hydroxyi group (by analogy to the

Meta-hydroxyl of cate~~~amines). Might

Not be a competing factor. Qur results indi-

Cate that. Contrary IO expectations, it is the

7-hydroxyl of various tlqs which is pre-

Dominantly methylated in rat brain.Que es la anoxia furth

Ermore. Catecholic dlqs do not even

Appear to be substrates for ~methylati~)n~~

VivoJJ. Based on this info~tion. The for-

Mation and action of the quinoidal tautom-

Ers should not be prevented by catechol-

D-methyltransferase.

In a number of studies, alcoholic damage

Has been likened to or actually resembles

Premature aging of the brairp. It is

Notewo~y that beta-carbolines. Eondens;

Tion products of indoleamines, may hr

Membrane cross-linking agents in the nor-

Mal aging of human lens tissues”. TIQ oxi-

D?:ion products could be conceived of as

Analogous agents in an alcohol-induced

Aging process, via the covalent mechanisms

Suggested. The co~~~~io~ox~dation

M~hanisms may also explnin the known

Individual variations in brain dama@ and

que es la anoxia

Psychological deficits among chronic

Alcoholics. That is. Subsequenr lo a general

Non-enzymatic condensation (TIQ forma

Lion) regulated by precursor availability,

The catalysed pr~uctiort of oxidized iso.

Quincclines might be a proccs\ uith signtfi-

Cant genetic differences betueen alcoholic

Individuals.

The TJQ/dlq/IQ rn~h~~srns outfined

Iould he occurring in other forms of

Rclcohol-induced tissue pathology as II 41.

Researchers have suggested that acetab

Dehyde (ach) may have a role in alcohohc

Liver injury. In view of the evidence for

Bepatic necrosis due to an ach-derived

TJQ in rats’“. It is possible that oxidized

TIQ species may be involved. AcH has

Been impheated in atcohohc cardiac dr.S

Ease; dfqs or 1qs derived from heart C.A\

que es la anoxia

And aldehydes or alpha-keto-acids could TV

Addittonal long-term pathological agent5 in

1 his peripheral organ.

In summary, in view of the avackcble ev i-

Dence, a discrete molecular n~e~h~tni~nl

,which could underlie aspects of aicohot

Induced brain and nerve damage is discus

3rd here. It is dependent on the intermtd-

Racy of ach (and possibly other carbony

Ntetabolites) and on the oxidative formation

Of minute 3mounts of neuronal dfqs.

Pi-oxides and their ~~t~nt~~~y ele~tr~~phi~t~

Tautomers which could serve as covalent

Btndinp agents over years of alcohol abuse.

Of course, this dots not obviate other

Nlcchanisms which might sontribute. Such

As direct ach and eroh membrane intrrac-

Tions. Chronic inhibition of essential brain

que es la anoxia

Trar;sport and protein synthesis”.

Ir~rnunog~ni~ factorp. Or even the rela

Tiveiy early suggestion of blood ‘sludp

Ing”Y. Efforts are underway in our labor-

Tory to test the validity of this ovemll chemi

Cal hypothesis in studies on TIQ ouidarivr

Conversions and effczts. And hopefully. The

Idea will provoke investi~atil~ns in other

La~~mtor~es.

The author acknowledges the helpful

Discussions with drs william nijm. Stan-

Ley lorens, J. Hannrgan and T. Origitano at

Loycla university, ur murray hamilton at

Sc~thr\c\~ f~untkcttc~n ior ke\carzh. San

€˜~ntc~r~ic~. Deba cyhara of chrc~go and dr

Wattcr os~vrald at the r.€˜nivcr