Memory Loss and Dementia (DrT lecture notes and on exorphins)

[liveonearth]

concerns about memory and dementia are ubiquitous
key factors: sleep, chemicals, age, breakfast, sugar, chew food, water, high HCL, declutter your mind (too many balls in the air), smoking
address these before assuming the pt is demented

TYPES
Cerebrovascular: multi-infarct, SID, SVCVD (Binswanger's dz)
Nutrit: Werneicke-Korsakoff
Degen: Pick's (frontotemporal dementia), huntinton's
Infx: Creutzfeld-Jakob, HIV
Alzheimer's 60%

diffuse lewy body dz DLBD
primary progressive aphasia (speech)
posteriar cortical atrophy (vision)

Trauma: SDH, boxer's dementia
Other: NPH, MS, dialysis, depression

top ten causes: AVDEMENTIA
alz
vasc
drugs, depress, delir
ehtanol
medical/metabolic
endocrine, ears, eyes, environ
neuro
turmor, toxin, trauma
infx, idiopathic, immun
amnesia, AI, apnea
VA-gulf war syndrome, PTSD

ALZHEIMERS
underreported, think 35 million now, 115 million by 2050
numbers increasing rapidly
depression is one of your largest ddx's
dx made definitively after death but how do we dx before death?
cognitive sx begin with cognitive
usu die of pneumonia, accidents
ALOIS ALZHEIMER 1895 proposed concept
irreversible, progressive
new test for screening he saw on CNN the other day
sx: early impairment in smell (leather, clove, menthol, strawberry, pineapple, natural gas, lemon, lilcc, soap, smoke) and short term memory
sx: later long term memory and ADL's affected, may become wild
BAS screening: DSAR above 27 is normal, below 22 is Alz??
tx: cholinesterase inhibitors slow progression by 6 months at most, time to get your affairs in order
tx: emotional (not SSRIs or TCAs, not well tolerated)
tx: antipsychotics to keep them under control in institutional settings
tx: stabilize blood sugar, hydrate, dental hygiene, regular bms
tx: diet: good efa's, some complex carbs and prob, low sat fat
tx: antiox supps, lots of supps not listed here

link to celiac: mayo clinic paper about it in Science Daily Oct 12 2006
prevention: avoidance of gluten if sensitive to it, forms EXORPHINS in brain
caution: beef, rice, broccoli also may form same compound in brain (this drT clinical no reference)
(aside: autism linked to poor digestion and leaky bbb)

curcumin now indicated for all chronic dz
reduces accumulation of amyloid in mice brains
phase II trials in US ongoing

expensive supps work great but nobody can afford these doses
phosphatidlycholine (toxic) 25g/day
phosphatidylserine 50-100mg sev x/day
very expensive tx, thousands $/month at these doses
acetyl-L-carnitine 3g/day

bone marrow stem cells converted to nerve cells
this research done at OHSU
injected these into elder brains and improved brain fx

cochrane report on statins just came out
they say we should not be giving statins
big backlash on the way

www.alz.org
www.eldercare.gov
DrT spends a lot of time helping family figure out what to do

eval potential elder dementia pt:
CBC, CMP, ASI/other hormone panels, refer, MMS exam (22 or less is dement, 27 or more is normal)
ddx: depression, delirium dt reduced drug clearance, dementia

delirium and tremors
think dt's, alcohol withdrawals-->tx: iv thiamine to stop withdrawals
panc pseudocysts usu dt alc and contain amylase

EXORPHINS info from http://xa.yimg.com/kq/groups/18630837/685088275/name/Exorphins.pdf
Current Pharmaceutical Design, 2003, 9, 1331-1344 1331
1381-6128/03 $41.00+.00 © 2003 Bentham Science Publishers Ltd.
Opioid Receptor Ligands Derived from Food Proteins
H. Teschemacher*
Rudolf-Buchheim-Institute for Pharmacology, Justus-Liebig-University of Giessen Frankfurter
Str. 107, D-35392 Giessen, Germany

Abstract: During the last two decades a variety of food protein fragments has been demonstrated
to elicit biological effects in various in vitro or in vivo test systems. A considerable part of these bioactive peptides are opioid receptor ligands , which may be regarded as exogenous
supplements to the endogenous opioidergic systems of the human organism. Most of these foodderived opioid receptor ligands are fragments of the milk proteins alpha-, beta- or kappa-casein,
alpha-lactalbumin, beta-lactoglobulin or lactotransferrin; however, also wheat gluten, rice
albumin, bovine serum albumin or hemoglobin, i.e. possible constituents of meat, and even a
protein from spinach could be demonstrated to contain fragments behaving like opioid receptor ligands. Practically all of these compounds display opioid agonist activity; only very few of them behave like opioid antagonists. Bioactive food protein derivatives have been termed " food hormones", which implies that these compounds display their bioactivities when released from food constituents, i.e. from their precursor molecules due to the action of gastrointestinal enzymes. The critical point in case of food protein-derived opioid receptor ligands is that only a
minority of their bioactive effects demonstrated as yet has been observed upon oral or intragastric administration of these peptides or their precursor proteins and that most of these studies have been performed in animals. Thus, in terms of "evidence-based dietary supplementation" more studies are needed to prove effects of food protein-derived opioid receptor ligands or their precursors after oral administration in humans and, moreover, to prove a benefit for the consumer's organism.
Key Words: Opioid receptor ligands; Opioids; Opioid peptides; Beta-casomorphins; Gluten exorphins; Hemorphins; Bioactive substances; Functional food.

INTRODUCTION
For a long time basic foodstuffs such as milk or bread
have just been regarded as "brick" or energy providers
required by the food consumer's organism. During the last
two decades, however, quite a few nutrients have been
shown to contain or to release under gastrointestinal
conditions "bioactive" substances apparently able to elicit
effects in the recipient's organism [1]. Since milk is a
foodstuff representing a "bridge" connecting the neonate's
and its mother's organism after their separation for quite a
long time, the detection of a variety of hormones and other
essential agents in mother's milk was, in principle, not
amazing [2, 3, 4, 5, 6]. However, during the last decade it
became clear that milk contains bioactive substances which
may be expected to elicit effects in the adult milk
consumer's organism as well - at least in the gastrointestinal
tract. The topic is drawing impressively increasing interest
as may be concluded from the reviews written on the field
during the last 5 years [7, 8, 9, 10, 11, 12, 13, 14].
Obviously, biologically active compounds derived from all
kinds of food have been searched for [15] - mostly in view
of their influence on intestinal functions [16], but also in
view of effects on the central nervous system [17]. Adverse
*Address correspondence to this author at the Rudolf-Buchheim-Institute
for Pharmacology, Justus-Liebig-University of Giessen, Frankfurter Str.
107, D-35392 Giessen, Germany. Fax: ++49-641-99-47609; E-mail:
Hansjoerg.Teschemacher@pharma.med.uni-giessen.de
effects of certain food constituents had to be considered also
[18] . Recently even a database of biologically active
peptide sequences has been offered [19]. Whereas terms
like "bioactives" [13], "food peptides" or "food hormones"
[20] or their short-cuts, e.g. "formones" [11] still refer to the
effects of food-derived bioactive substances on the food
consumer's organism , more recently coined terms such as
"functional foods" or "nutraceuticals" [21, 22, 23] indicate a
considerable interest in "formone"-containing "functional
foods" - not only signalled by their consumers, but also by
their producers.

From the very beginning of the development outlined
above there was a considerable interest in screening basic
foodstuffs for opioids potentially contained therein. In view
of the peptide character of endogenous opioids found in the
mammalian organism, food protein cleavage products
appeared to be candidates. The search for food-derived
opioid peptides was, in fact, successful [24] .
In this review, the chase for food protein-derived opioid
agonists or antagonists ending up with their demonstration
and preliminary pharmacological characterization will be
described under a historical point of view - with emphasis
on the significance of food-derived opioid peptides as
exogenous opioid receptor ligands in relation to the
endogenous opioidergic systems of the human organism.
Proven and potential physiological as well as pharmacological, i.e. nutraceutical significance of food protein-derived
opioid receptor ligands will be discussed.1332 Current Pharmaceutical Design, 2003, Vol. 9, No. 16 H. Teschemacher

OPIOIDERGIC SYSTEMS OF THE HUMAN ORGANISM

Endogenous opioidergic systems of the human organism
consist of opioid receptors and their ligands, endogenous
opioids with alkaloid or with peptide structure. For
extensive review up to the year 1992 see Handbook of
Experimental Pharmacology, Volumes Opioids I and II [25]
; short-cut and updated information about the field as far as
relevant in context with this review has been presented as
well [26] .

Opioid Receptors
Opioid receptors have been found in the central and in
the peripheral nervous system, in the immune system and in
the endocrine system of mammals [27, 28, 29].There are
three types of opioid receptors, m- , d- and k-opioid
receptors; m1/m2 , d1/d2 and k1/k2 subtypes have been
reported as well [30, 31, 32]. The chromosomal location of
the receptor genes, OPRM (m), OPRD (d) and OPRK (k),
are 6q24-25, 1p34.3-36.1 or 8q11-12 , respectively [32, 33].
A fourth receptor sharing a high degree of structural homology with those conventional opioid receptors, displaying, however, quite distinct pharmacological properties is the
Orphanin FQ / nociceptin receptor, N/OFQ [34] . Further
names for the receptors, MOP, MOR, OP3 (for m), DOP,
DOR, OP1 (for d), KOP, KOR, OP2 (for k) or NOP, NOR,
ORL1 (for N/OQF) have not been widely accepted as yet
[33, 35] . Opioid receptors belong to the family of G
protein-coupled receptors and their activation results in
adenylate cyclase inhibition (Gi), K+ channel activation
(Gi/o) or Ca++ channel inactivation (Go) [31, 32, 36, 37] .

Endogenous Opioid Receptor Ligands
Endogenous opioid receptor ligands may have alkaloid
or peptide structure. There is only limited information about
endogenous "opioid alkaloids" [38, 39]. By far most of the
endogenous opioid receptor ligands are peptides; they
almost exclusively behave like agonists at opioid receptors.
These "opioid peptides" may be divided in two groups,
"typical" and "atypical" opioid peptides.
Typical opioid peptides are liberated from three
precursor proteins, from proenkephalin (PENK), from
proopiomelanocortin (POMC) and from prodynorphin
(PDYN). From PENK the enkephalin pentapeptides (and
longer fragments containing the enkephalin sequences) ,
from POMC the endorphins (after their cleavage from the
precursor they may be N-terminally acetylated) and from
PDYN the dynorphins (and further fragments such as
neoendorphins) are released. Like the opioid receptors,
PENK, POMC and PDYN are mainly expressed in the
central and in the peripheral nervous system, in the immune
and in the endocrine system [40, 41] . As a structural
characteristic, all typical opioid peptides have the same Nterminal amino acid sequence, Tyr-Gly-Gly-Phe, which is their fragment able to interact with opioid receptors.
Atypical opioid peptides [42] differ from typical opioid
peptides in view of structure and precursor proteins. All
atypical opioid peptides have a N-terminal Tyr residue, but
the rest of the N-terminal amino acid sequence is not
identical with that of the typical opioid peptides and shows
considerable variation. Their precursor proteins, e.g.
hemoglobin, appear to be quite different in terms of
distribution or function in comparison with PENK, POMC
or PDYN [42] .

Functional Significance of Opioidergic Systems
Receptors and ligands of the endogenous opioidergic
systems are biosynthesized within cells, tissues or
compartments of the immune system , the endocrine system,
the central and the peripheral nervous system. As
compatible with this distribution, the ligands, as far as
administered like drugs, elicit effects on their receptors
located within these systems , most of wich are well-known
classical opioid effects such as antinociception, respiratory
depression, sedation, gastrointestinal motility reduction, etc.
In particular on cells of the immune system, however,
additional effects are elicited - apparently due to the opioid
peptides' additional interaction with target molecules not
identical with opioid receptors [43, 44] . However, for most
of these endogenous ligands it is not clear as yet, under
which conditions they interact with opioid receptors.
Although opioidergic systems appear to be involved in a
wide variety of functions such as nociception,
cardiovascular regulation, respiration, neuroendocrine,
neuroimmune or various behavioural activities, etc. [25, 45]
, inactivation of PENK, POMC, PDYN, MOR, DOR and
KOR genes in mice by homologous recombination (gene
knockout mice) revealed very interesting, but still limited
information about the physiological significance of
opioidergic systems in mammals [46] . Information about
consequences of gene deficiencies in humans is still
meagre. POMC gene mutations just led to early onset severe
obesity, red hair pigmentation and adrenal insufficiency
[47] , and allelic variation in the PDYN gene promoter as
studied did not prove to be correlated with physiological or
pathophysiological phenomena such as schizophrenia or
heroin addiction [48, 49] . Variations in the human MOR
gene appeared to correlate with heroin addiction [50] or
with idiopathic absence epilepsy [51] , whereas human
DOR gene variations as studied did not correlate with
heroin or alcohol dependence [52] .

Food Protein-derived Opioid Receptor Ligands: Exogenous Supplements to Endogenous Opioidergic Systems
Opioid receptor ligands not biosynthesized by the
human organism were used thousands of years before the
detection of their endogenous counterparts; as constituents
of opium they were used as analgesics or antidiarrhoics and
their major representative, morphine, was isolated from
opium around 1800 by a pharmacist, F. W. Sertürner.
Morphine and some other opioid alkaloids are still the only
analgesics effective for treatment of patients with extremely
severe pain. After the demonstration of opioid receptors in
1973 as well as, during the following years, of a series of
peptide ligands cleaved from precursor proteins in the
human organism the interest in exogenous opioid receptor
ligands shifted from opioids of alkaloid structure to opioids
of peptide structure. In fact, a series of such exogenous
opioid peptides has been demonstrated, which just can beOpioid Receptor Ligands Derived from Food Proteins Current Pharmaceutical Design, 2003, Vol. 9, No. 16 1333
regarded as exogenous supplements to the endogenous
opioidergic systems (Fig. 1) ; these exogenous opioid
receptor ligands were food protein cleavage products
exclusively [24] - most of them derived from milk proteins
[26, 53, 54, 55, 56] . They proved to be atypical opioid
peptides exclusively [42, 57] . It appears more than likely
that among these exogenous opioid receptor ligands at least
the milk protein-derived opioid peptides are essential
supplements of the opioidergic systems of the recipient's
organism (Fig. 1).

SEARCH FOR FOOD PROTEIN-DERIVED OPIOID RECEPTOR LIGANDS
The chase for exogenous ligands of opioid receptors
accompanied the chase for their endogenous counterparts
from the very beginning of the research on opioidergic
systems. Screening of basic foodstuffs for materials with
opioid agonist or antagonist activity soon succeeded in the
demonstration and subsequently in the pharmacological
characterization of food protein-derived opioid receptor
ligands.

Screening Basic Foodstuffs for Food Protein-derived
Materials with Opioid Agonist or Antagonist Activity
Most basic foodstuffs, i.s. milk, cereals, maize, rice, soy,
eggs or blood as a constituent of meat were screened for
protein fragments with opioid agonist or antagonist activity
(Table 1). From a historical point of view credit should be
given for pioneer work to the group of Werner Klee and
Christine Zioudrou [58] , who conducted the first
systematic study on this field or to Seymour Ehrenpreis'
group [59] for raising the first finding on a milk proteinderived opioid-like acting material. The first food constituent identified as an opioid receptor ligand was a
bovine beta-casein fragment [60] later followed by the
identification of further opioid agonists or antagonists
derived from milk proteins [61] .
Two strategies were used for identification of the
opioids. Frequently, preparations of food, mixtures of food
proteins or proteins isolated from food were subjected to
peptic, tryptic, or chymotryptic hydrolysation or to
digestion by various gastrointestinal enzymes. The
hydrolysates were screened for materials with opioid
activity using either an adenylate cyclase test [58] or one of
two bioassays employed very frequently for testing
materials for opioid activity, i.s. the guinea pig ileum
longitudinal muscle myenteric plexus preparation ("strip")
or the mouse vas deferens preparation; a material was
assumed to contain a peptide with opioid agonist activity,
when its inhibitory effects on these organ bath preparations
could be antagonized by the opioid antagonist naloxone.
Further, radioligand competition assays with opioid receptor
preparations were also used for assessment of opioid
properties. Opioid-like behaving materials were subjected to
chromatographical purification and isolation procedures and
the isolated peptides, in most cases, were identified by
Edman degradation techniques and amino acid analysis.
Synthesis of the identified peptide was an additional step
necessary for confirmation of the peptide's sequence. A
second method proved to be faster: Any food protein
fragment expected to interact with opioid receptors due to a
Tyr residue in N-terminal position was synthesized and
tested for opioid activity using the aforementioned
techniques. In case of a positive result, evidence for its
release under gastrointestinal conditions had to be provided
subsequently.

In fact, a variety of enzymatic digests of milk proteins,
a-casein [58, 62, 63, 64] , b-casein [60, 65, 66, 67, 68, 69,
70, 71] , k-casein [72, 73], a-lactalbumin [58, 70, 74] , blactoglobulin [70] , and lactotransferrin [58, 73] were shown
to contain materials with opioid agonist or antagonist
activity, which subsequently were all identified (Table 1).
The opioid material contained in the peptic hydrolysate of
a-casein [58] appeared to be very pure from the very
beginning [58] as it apparently also was the case with the
opioid demonstrated in a peptic bovine serum albumin
digest [58]; however, their identification took considerable
time - more than a decade [62, 63, 75] .
Also peptic hydrolysates of proteins from wheat, barley,
oats, rye, maize or soy were screened for opioid agonist or
antagonist activity very early [58] and indeed gluten,
gliadin, hordein and zein hydrolysates proved to contain
materials with opioid agonist activity as shown in the
adenylate cyclase test [58]. The peptides from gliadin and
gluten were identified later [77, 78, 79, 80]; this, however,
took never place with the materials from hordein and zein.
Also a tryptic digest of rice seeds was successfully screened
for materials with opioid receptor ligand properties; the
material was identified and appeared to show opioid agonist
as well as antagonist properties [76].
Peptic ovalbumin and g-globulin hydrolysates tested as
well did not contain opioid agonist or antagonist activity
[58] , but enzymatic digests of bovine serum albumin [58,
75] and of whole bovine blood did contain opioid-like
acting materials, which were shown to be fragments of
albumin [75] or hemoglobin [81], respectively.

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