|
Trail:
Ecosystems
page 2
page 3
page 4
page 5
page 6
page 7
page 8
page 9
|
 Scientific
papers - Ecosystems - page 7
The
clinical perspective of Mn intoxication
Chronic Mn toxicity first reared its insidious, ugly head in the
Byzantine era, when Black Magic was referred to as 'Mangania' -
the term for Mn ore (3). Mn psycho-neuro-toxicity was
subsequently recognised within the more mainstream world of
medicine when those occupationally exposed to Mn ores in the
mines of Chile, India, N Africa, N America, the Isle of Guam and
Japan developed a bizarre delayed neuropsychiatric condition
known as 'locura manganica' or 'manganese madness' between 1-24
years after starting work in the mines (3). The initial
psychiatric phase of the disease was invariably followed by an
irreversible progressive neurodegenerative phase; the two stage
syndrome becoming widely accepted as the characteristic clinical
scenario encountered in chronic manganese intoxications of
miners exposed to Mn dioxide dust (97, 104, 105, 11).
Interestingly, the
sequence and types of symptom exhibited in the class of Mn
intoxication encountered in miners bear close resemblance to the
new strain CJD/BSE/Kuru types of TSE (41, 106, 107), whilst the
other less common class of Mn intoxication exhibited by workers
in the ferro-manganese plants of North America (105, 108, 11, p.
20) does not present with such a clearly defined, broadranging
psychiatric phase at the onset of symptoms - a clinical profile
more akin to the symptomology of sporadic TSEs (41).
Symptoms such as
cortical blindness and convulsions which characterise the later
stages of sporadic CJD (although absent in the Kuru TSE) (41) do
not appear to have been reported in any publication covering Mn
neurotoxicity despite reports of upper cortical involvement in
the pathology and symptomology of several case studies.
However, epileptic
convulsions have been associated with the clinical
manifestations of CNS Mn deficiency (4), suggesting a pivotal
role for Mn in maintaining neurochemical homeostatis. It is
possible that an abnormal CNS accumulation of an Mn3+/Mn4+, or
simply an Mn2+ species, within a Mg2+ deficient environment (4)
(as recorded in TSE regions (Table 1)) could lead to the
inactivation of the Mg/Mn dependent enzyme glutamine synthetase
and/or a break down in the stabilisation of its molecular
conformation (109,4) (glutamine synthetase is essential for
converting neurotoxic glutamate into glutamine inside the
astrocytes (7)), thus leading to disruption of the neurochemical
equilibrium in the frontal zones, which, in turn, increases the
risk of convulsions.
Common symptoms of
chronic Mn intoxications (3,11,97,104,107) are duplicated in
TSEs (41,106); e.g.asthenia, loss of balance, cough, hypersomnia,
insomnia, anorexia, oculogyric crises, loss of libido,
forgetfulness, lack of concentration, depression, irritability,
confusion, headache, unexplained generalised pain, slurred
speech, mutism, emotional lability, weeping, excessive
laughter/childish smiling, euphoria, salivation, facial
seborrhea, excessive sweating, delusions, withdrawal,
hyper-activity, paranoia, hallucinations, psychoses/insanity,
immaturity, compulsive actions, clumsiness, self neglect,
aggressiveness, hypokinesia, rigidity, tremors, upper and lower
motor complaints such as aphasia, dystonia, choreoathetoses,
muscle cramps, speech disturbance, abnormal shuffling or
cock-walk gait and postural reflexes, myoclonic jerks, rigidity,
cogwheel on the wrists, ataxia, and, neurological disturbances
involving a combination of pyramidal, extra pyramidal and
cerebellar symptoms.
The common occurrence
of somewhat unique symptoms such as 'unmotivated spasms of
laughter/childlike grinning' in both Mn intoxications
(3,97,104,105) and nv CJD/Kuru (41,107) is interesting. Indeed,
kuru has been described as the 'laughing death' (107), whilst
the entire workforce of some Mn mines have been reported to
burst into prolonged bouts of unmotivated laughter (105)!
There is also
variation in the period between initial occupational involvement
with Mn and the emergence of the clinical phase of the disease.
Miners may develop the initial symptoms of Mn intoxication
between one and twenty four years after first becoming
occupationally involved with Mn (97,104,105), whilst others do
not develop the neurodegenerative phase of the disease until
several years after ceasing employment in the mines - at a time
when there is considerably less measurable Mn in their systems
than the levels found in healthy active miners (105).
It would appear that
the Mn factor does not perform any pathogenic role in
'propelling' the secondary neurodegenerative stages of the
disease. This is supported by the fact that therapy with an Mn
chelator during this secondary stage fails to arrest the disease
(112). However, Mn chelators can successfully arrest the
syndrome during its initial psychiatric stages (112), often
leading to permanent remission.
Whilst such a
scenario of self perpetuation indicates the presence of free
radical chain reactions as the driving force behind the later
stages of Mn encephalopathy, it also elucidates possible common
pathogenic mechanisms underlying the delayed, so called
'incubation' period that are shared by Mn intoxications and
prion diseases.
The
putative pathogenic mechanisms of Mn intoxication underlying
TSEs
The CNS pathogenic mechanisms of Mn intoxication are
consequently little understood, although researchers consider
that they hinge upon a complex multifaceted series of auto
oxidative chain reactions - probably initiated via Mn's highly
reactive trivalent species, Mn3+, which has been shown to
readily oxidize catecholamines 'in vitro' (7,29,11).
Such a putative
pathogenic mechanism encompassing Mn initiated radical eactions
explains the widespread disruption of several classes of CNS
receptor, Ca channels, signal transduction cycles and second
messenger sythesis that has been noted in chronic Mn
intoxications (7). Mn also accumulates in the mitochondria
during intoxication where it disrupts the homeostatis of Ca
channels raising intracellular levels of free Ca involing
further oxidative stress (7).
Interestingly, Mn2+
also competes with Mg2+ for the site on the ATP complex. The Mn-ATP
bond is strong, thus explaining how Mn displaces catecholamines
from their bonding to the ATP complex in the storage vesicles of
chromaffin granules in the adrenal medulla (110,3).
80% of the total Mn found in the brain is tied up in sctivating
the manganoenzyme glutamine synthetase which is found
exclusively in the astrocytes (7); inferring that abnormal
radical reactions derived from Mn3+ overloading in the CNS would
largely remain confined to the astrocytes.
Interestingly, Brown
et al. have demonstrated that type 1 astrocytes express PrP
relatively intensively (111). Astrocytes are invariably
activated in response to proliferating microglial cells during
the early stages of TSE (111). The failure of astroglial cells
to respond correctly in TSE suggests that the conformational
development of PrP with PrP expressing type 1 astrocytes has
been corrupted (eg; due to a putative Mn3+ substitution at PrP's
oxidative stress by SOD1 in astroglial cells. Brown et al (111),
has demonstrated that the activation of astrocytes and
microglial is an essential prerequisite of TSE pathogensis (NB;
astrogliosis is a fundamental pathological feature of TSEs
(41)).
Glutamine synthetase
performs a vital role in catalysing the conversion of the
excitatory amino acid glutamate into glutamine after it has been
carried from the synaptic cleft into astrocytes by a high
affinity uptake system (7). Interestingly, the conformational
stability of glutamine synthetase is regulated by a complex
equilibrium involving Mn2+ and Mg2+ (109). This elucidates a
further putative neurotoxic mechanism stemming from further
putative neurotoxic mechanism stemming from Mn overload, where
an excess of trivalent Mn in the astrocytes (coupled to the
additional complication of Mn deficiency recorded in TSE
ecosystems) (Tables 1 & 2) disrupts the biochemical pathway
that mediates the structural stabilisation and activation of
glutamine synthetase, leading to an abnormal accumulation of the
highly neurotoxic glutamate instead of its normal metabolic
conversion product glutamine. Glutamate is excitotoxic to
neuronal membranes and various ionic channels which increases
intracellular levels of free Ca leading to a variety of radical
cascades.
Interestingly,
glutamate overloading plays a significant role in the
pathogenesis of membrane disruption/degeneration manifested in
TSEs (41,89,96) and other neurodegenerative diseases, such as
ALS, where glutamate metabolism (113) and its uptake at the
glutamate AMPA/Kainate receptors are both impaired (114). Mn2+
substitutes for Ca at the Ca channels and is recognized as the
most potent inhibitor of kainic acid binding to forebrain
membranes (115).
Other biochemical
facets of TSE pathogenesis such as the increased capping of
cells with the lectin, concanavalin A (19), and the 3 1/2 fold
increase in the surface expression of PrP invoked by the lectins,
concanavalin A and phytohaemaglutinin (18), could be explained
by the key role that Mn performs in activating these lectins
(116,117). Mn activation of lectins like concanavalin A acts as
a critical prelude to the subsequent binding of calcium to this
lectin, as well as to the subse quent interaction of the lectin
with its specific cell surface glycoprotein target (117).
Removal of Mn abolishes the glycoprotein binding properties of
most lectins.
Once levels of available Mn exceed its normal threshold in the
CNS, Mn could overactivate increased amounts of lectins like
concanavalin A; a lectin which is known to interact with the
membrane glycoprotein PrP (18). Con A is also known to bind to
glycosaminoglycans (118); unbranched polysaccharides that are
well recognized to bind to PrPc, protecting the protein against
bonding to the abnormal PrPsc, which, in turn, appears to
protect the PrPsc 'infected' mammal against the development of
clinical TSE (5). An overloading of Mn could therefore account
for yet another crucial primary role in TSE pathogenesis by
overactivating lectins that bind to glycosaminoglycans, which,
in turn, inactivates the ability of these glycosaminoglycans to
bond to PrPc, thus breaking down the protective mechanism
designed to safeguard PrPc against its putative lethal
conjugation onto PrPsc.
The quantity of
lectins in the animal diet could also present a TSE risk factor.
Lectins are relatively stable, heat resistant naturally toxic
proteins found in peanuts, beans (locust, kidney and haricot),
soya, alfalfa, rice bran, peas, lentils, wheat, bulbs, snails,
etc. Interestingly, The majority of these foodstuffs were
incorporated into the concentrated rations of UK dairy cattle
during the BSE era (119). In particular, the temporal dynamics
of annual UK usage of field beans in animal feed rations (119)
correlates with the temporal dynamics of annual incidence rates
of BSE in the UK (see Fig. 8). A total of 37,800 tons of field
beans were used in animal feed rations in 1984, rising to a peak
of 247,400 tons in 1989, then dropping to 85,600 tons by 1995.
Once TSE-susceptible animals are dependent upon food supplies
that are simultaneously high in both manganese and lectin
content, the risk of developing TSE could be significantly
increased.
The
aetiological association of Mn overloading with other
neurodegenerative diseases
Some researchers consider that the secondary irreversible
neurodegenerative stages of chronic Mn intoxication is a form of
Parkinson's disease (PD) (11). Despite the similarities, the
pattern of pathological damage in most cases of Mn intoxication
deviates from the exclusive extrapyramidal pathology of PD.
Furthermore, Mn pathology rarely encompasses the substantia
nigra (11,97) 97 the 'nidus' of neurodegeneration in PD. However
high incidence rates of amyotrophic lateral sclerosis (ALS) and
PD have both been recorded amongst Mn miners on Guam and in
Japan (115,120,121). Serum Mn levels are frequently elevated in
ALS/PD victims (14,122,123), and have been recorded more
recently in the serum of those suffering from psychoses,
rheumatoid arthritis and Alzheimer's dementia (4, p. 189) (6) -
conditions which have been theoretically associated with a prion
induced pathogenesis.
Yase had analysed the
soils/plants in the renowned South Pacific cluster of ALS/PD/MS/Alzheimer's
type dementia on Guam, the Ku Peninsula (Japan) (115, 120) and
West New Guinea and found that high levels of the divalent
cations, manganese/aluminium were recorded in all regions.
Spencer et al. (124)
hypothesized on the presence of a key environmental trigger
factor underlying the pathogenesis all of these
neurodegenerative diseases in the South Pacific cluster, but
they plumped for a neurotoxic excitatory amino acid in the
natives' diet of cycad fruit as the putative causal agent
operating within a multifactorial aetiological template, having
rejected the possibility that the high levels of Mn/Al cations
found in the indigenous terrain could accumulate in cycad fruit
and chronically intoxicate the natives causing neurodegenerative
disease to surface in later life.
Fig. 8
Comparison between the month of birth of confirmed cases of BSE in
the UK and annual tonnages used of the cation-based pesticides Maneb
(containing Mn) and Diquat in the UK. BSE and pesticide data sourced
from
MAFF's 'BSE in Great Britain: a progress report' (Dec 1998) and MAFF's
pesticide usage surveys.
Interestingly, there is a high incidence clustering of MS and
ALS amongst some of the subsistent farming communities who used
to live directly 'off the land' within the Mn-rich scrapie
endemic regions of Iceland (125).
Spencer et al. (124)
and Gadjusek (126) have elucidated common pathogenic
denominators between PD, ALS, AD, etc., suggesting a common
environmental trigger factor shared by all of these diseases.
Some of the
pathological similarities noted in ALS, AD, and PD are also
observed in TSE pathology (129,41). Furthermore the pathogenesis
of ALS demonstrates some specific biochemical facets that are
shared by TSEs; such as a high turnover of the Mn-containing
metalloenzyme (3,4) arginase (127) in the primary stages of
pathogenesis of both diseases. High levels of available Mn may
'switch on' the increased expression of arginase in the early
stages of these diseases. Interestingly, a strain of ALS was
induced in young calves following intracerebral inoculation with
PrPsc CNS homogenate (128), whilst a specific class of CJD known
as amyotrophic CJD exhibits a pathology which combines
idiosyncratic features from both ALS and CJD (120, p. 318).
Other CJD cases have combined Alzheimer's neurofibrillary
tangles or Parkinson's Lewy bodies with the usual TSE features
(130).
Whilst some
researchers have putatively linked cations such as manganese,
aluminium and calcium to the aetiology of these
neurodegenerative diseases found on Guam and elsewhere across
the world, Mn intoxication has hitherto never been previously
associated with TSE pathogenesis.
This theory proposes
that cations such as Mn or Nickel, in their trivalent context,
may play a primary role as the infectious transmissible agent in
the aetiology of TSEs, providing the other essential TSE
prerequisites are fulfilled, e.g. TSE susceptible genotypes
being chronically exposed to Mn/nickel during Cu/Fe deficiency
states. Conventional neurodegenerative diseases, as apart from
TSEs, will develop in contexts where the cation-over- loaded
individual possesses optimum levels of Cu in their CNS; thereby
ensuring that an adequate supply of Cu occupies PrP's copper
domain, thus protecting PrP against invasion by foreign cations
and the resulting induction of an abnormal conformational change
of PrP.
Back
to the top
Back
to page 6
|
