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ISSN 00063509, Biophysics, 2010, Vol. 55, No. 1, pp. 71–76. © Pleiades Publishing, Inc., 2010.
Original Russian Text © I.Ya. Podolski, Z.A. Podlubnaya, O.V. Godukhin, 2010, published in Biofizika, 2010, Vol. 55, No. 1, pp. 88–94.
71
12
INTRODUCTION
Fullerenes C
60
are carbon nanoparticles with
unique physicochemical and biological properties.
Investigation of fullerenes appears as one of the lead
ing directions of nanobiotechnology and nanomedi
cine. The action of fullerenes on
β
amyloids, neurons
and cognitive processes is a new problem that throws a
bridge from nanotechnology to neuroscience.
Buckminsterfullerene (for short, fullerene C
60
)
consists of 60 atoms of carbon positioned at the verti
ces of regular hexagons and pentagons forming a sym
metrical hollow sphere of less than 1 nm in diameter.
The carbon atoms are connected between themselves
by conjugated double bonds creating on the entire sur
face of the molecule a unified system of nonlocalized
π
electrons.
Fullerenes were discovered by H. Kroto, R. Smal
ley and R. Curl in 1985. In 1996 the authors were
awarded the Nobel Prize in chemistry. The captivating
1
Abbreviations
: C60, fullerene; ROS, reactive oxygen species; Ab,
amyloid bpeptide; FWS, colloidal water suspension of
fullerene; AD, Alzheimer’s disease; NMDA, NmethylD
aspartate; AMPA, aamino3hydroxy5methyl4isoxazole
propionic acid; LTP, longterm potentiation; PS, population
spike; PVP, polyvinyl pyrrolidone; AIDS, acquired immune
deficiency syndrome; HF, high frequency.
2
Editor’s Note
: This text is a meticulously prepared equivalent of
the original Russian publication with all its factual statements,
terminology, phrasing and style, so the reader may more clearly
recognize the major problems with this area of scholarly activity.
story of the discovery of this “star molecule” is pre
sented in the Nobel lecture of R. Kroto [1].
Hydrophobicity, spherical shape of the molecule,
unusual redox properties allowing attachment of up to
six electrons, and low toxicity stimulate the investiga
tion of the biological properties of this surprising mol
ecule [2–4]. One of the main biological properties of
fullerene C
60
is the ability to quench free radicals, to
behave as a “sponge of free radicals.” Application of
this property is prevented by the exceptionally low sol
ubility of C
60
in water and aggregation of its nanopar
ticles. Dissolution strongly affects the quenching of
reactive oxygen species (ROS), and this is necessary to
be taken into attention during characterization of var
ious preparations and evaluation of their action [3, 5].
One of the properties of fullerenes is permeability
through model lipid membranes exceeding all other
molecules [6, 7].
Recently started was the introduction of nanotech
nology into neuroscience, which is rapidly developing
[8, 9]. One of the promising directions is the investiga
tion of the mechanisms of the neuroprotector action
of fullerenes and the possibility of developing on their
basis medications acting on the key molecular mecha
nisms of neurodegenerative diseases [8, 10].
ANTIAMYLOID ACTION OF FULLERENES
In recent years a strong influence has been dis
closed of nanoparticles on aggregation of the amyloid
CELL BIOPHYSICS
Fullerenes C
60
, Antiamyloid Action,
the Brain, and Cognitive Processes
I. Ya. Podolski
a
, Z. A. Podlubnaya
a
, and O. V. Godukhin
a
,
b
a
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences,
Pushchino, Moscow Region, 142290 Russia
b
Pushchino State University, Pushchino, Moscow Region, 142290 Russia
Email: podolski.igor809@gmail.com
Received October 9, 2009
Dedicated to the memory of a remarkable scientist
and humanist Levon Mikhailovich Chailakhyan
Abstract
—A short review of investigations along a new line: the antiamyloid action of fullerenes C
60
and cor
rection of disturbed cognitive processes is presented. The prospects for the development of drugs based on
fullerenes acting on the key molecular mechanisms at the early stage of Alzheimer’s disease are discussed.
Key words
: fullerenes C
60
, antiamyloid action, neuron, memory, Alzheimer’s disease, neurodegen
erative diseases
DOI:
10.1134/S0006350910010136
72
BIOPHYSICS Vol. 55 No. 1 2010
PODOLSKI et al.
β
peptide [11–14]. The first work was performed by
Kim and Lee in 2003. The authors showed that in a
water solution the 1,2(dimethoxymethano)fullerene
quenched the fluorescence of thioflavin T bound with
amyloid
β
peptide (1–40) (A
β
1–40
). The effect was
significantly stronger pronounced than in other inhib
itors of A
β
aggregation [15]. The authors supposed
that the fullerene binding with the hydrophobic region
of A
β
1–40
(motif KLVFF), precluding aggregation of
monomers. Recently we have for the first time by a
visual method (with the aid of highly resolving elec
tron microscopy) shown the strong influence of
fullerenes C
60
on amyloidogenesis of A
β
peptides. In
the experiments in vitro addition of fullerene leads to
decoration of amyloid fibrils by small spherical aggre
gates of fullerene. A colloidal water suspension of
fullerene (C
60
FWS) added before formation of mature
amyloid fibrils (helically twisted ribbons) of A
β
25–35
pep
tide prevented their formation. The fullerene destroyed
as well the peptideformed fibrils (see Fig. 1) [16], and
exerted the same action on fibrils of A
β
1–42
[17]. Beside
that, it was shown that C
60
FWS and a polycarboxyl deriv
ative of fullerene, C
60
Cl(C
6
H
4
CH
2
COONa)
5
, destroyed
mature amyloid fibrils of muscle Xprotein and pre
vented formation of new fibrils [18]. Our data allow
one to suggest that amyloid peptides represent the tar
get of fullerene action. It should be underscored that
strong antiamyloid action is exerted by small aggre
gates of fullerene and its watersoluble derivatives. It
appears that hydrophobic interactions of fullerenes
with amyloid
β
peptides and Xprotein fibrils lie in the
basis of their antiaggregation action. Our data allow
one to suggest that amyloid peptides represent the tar
get of fullerene action. Of great interest is the investi
gation in vivo of the action of fullerenes on
β
amino
loids. This work has been just initiated by us.
The influence of nanoparticles on
β
amyloids
causes great interest. Thus in work [11] during con
duction of experiments in vitro it was shown that poly
ethylene glycol phospholipid nanomycelles destroyed
fibrils of A
β
1–42
. In distinction from this, nanoparticles
of titanium dioxide strengthened the aggregation of
A
β
1–42
, causing amyloidogenic action [12]. The
authors suggested that certain nanoparticles can be an
etiological factor of the spontaneous form of Alzhe
imer’s disease (AD). The causes of the spontaneous
form of AD are unknown. The supposition about the
role of certain nanoparticles in the etiology of AD is
the subject of further investigations.
Interaction of proteins and nanoparticles is a
highly specific process depending on the properties of
the surface of proteins and nanoparticles. Of critical
significance is the curvature of the nanoparticle sur
face. This hypothesis explains the mechanism of the
different influence of nanoparticles on the formation
of A
β
fibrils [13, 14].
INFLUENCE OF FULLERENES
ON BRAIN NEURONS
What action do fullerenes exert on brain neurons?
On a culture of rat embryo brain neurons, polyhydrox
ylated fullerenes fullerenols (C
60
(OH)
18
) suppressed
the binding of subtypes of ionotropic glutamate recep
tors: NmethylDaspartate (NMDA),
α
amino3
hydroxy5methyl4isoxazole propionate (AMPA)
and kainate ones and lowered the level of intracellular
calcium [19]. In sections of rat hippocampus a colloi
dal water suspension of fullerene C
60
(C
60
FWS) in
which both separate molecules and associates thereof
were present [20], at a low concentration (7
×
10
–6
, 7
×
100 nm
100 nm
100 nm
(a)
(b)
(c)
Fig. 1.
Electron micrographs of aggregated A
β
25–35
pep
tide, colloidal water solution of fullerene (C
60
FWS) and
A
β
25–35
peptide upon addition of C
60
FWS. A
β
25–35
peptide incubated for 24 h at 37
°
C. Helically twisted rib
bon fibrils of 26 nm diameter (shown with arrows) (a).
Spherical aggregates of C
60
FWS of 5–40 nm diameter and
their conglomerates (b). Incubation of A
β
25–35
peptide
with C
60
FWS at a molar relationship 6:15. All fullerene
aggregates are bound with short protofibrils of A
β
peptide,
shown with arrows (c). Scale, 100 nm [16].
BIOPHYSICS Vol. 55 No. 1 2010
FULLERENES C
60
, ANTIAMYLOID ACTION, THE BRAIN 73
10
–5
mg/mL) significantly raised the activity of pyra
midal neurons, the basic cell elements of the hippoc
ampus, without disturbing the development of long
term potentiation (LTP) (see Fig. 2). At a higher con
centration (7
×
10
–3
mg/mL) the fullerene did not
influence the activity of pyramidal neurons and sup
pressed LTP [21]. The genesis of the population spike
(PS) evoked by stimulation of glutamatergic synaptic
inputs from Schaffer collaterals depends both on acti
vation of postsynaptic AMPA receptors of glutamate
and on potentialdependent Na
+
channels of pyrami
dal neurons. A factor of initiation of the development
of LTP of synaptic transmission in the CA1 field of the
hippocampus is the activation of NMDA receptors
[22]. We suppose that nonmodified fullerene exerts
another action than polyhydroxylated fullerenes and
at low concentration, without influencing the activity
of NMDA receptors, is capable of either selectively
raising the efficiency of transmission of the synaptic
signal mediated by AMPA receptors or enhancing
activation of potentialdependent Na
+
channels of
postsynaptic pyramidal neurons. Further investiga
tions of this question are required.
ROS and glutamate excitotoxicity represent the
leading factors of the pathogenesis of many grave and
widespread brain diseases: neurodegenerative dis
eases, brain circulation disorders, epilepsy [23]. In
hippocampal sections, hydrogen peroxide and
cumene hydroperoxide reversibly suppressed the
amplitude of the PS of pyramidal neurons in the CA1
field. Introduction of fullerenol at low concentration
(0.1 mM) prevented the damaging action of ROS.
Fullerenol restituted the synaptic conductivity at a
concentration an order of magnitude lower than defer
oxamine, an iron chelator [24]. On a culture of corti
cal neurons it was shown that carboxyfullerenes low
ered the excitotoxicity caused by stimulation of
NMDA and AMPA receptors and suppressed apopto
sis caused by A
β
1–42
[10]. On a culture of phenochro
mocytoma neurons, fullerenol at a concentration of
0.1–1.0
μ
M decreased the level of free calcium in the
cytosol elevated by A
β
25–35
, a neurotoxic fragment of
A
β
1–42
[25].
Thus, in experiments in vitro fullerene elevated the
activity of pyramidal neurons—the basic cell elements
of the hippocampus. On a culture of neurons and hip
pocampal sections the fullerene derivatives (fullerenol
and carboxyfullerene) exhibited antioxidant action
and lowered the neurotoxic action of
β
amyloids. One
of the cell targets of fullerene action appear to be the
ionotropic glutamate receptors.
INFLUENCE OF FULLERENES
ON THE BRAIN AND DISORDERS
OF MEMORY
Nanoparticles during nasal respiration, bypassing
the hematoencephalic barrier, through the olfactory
nerves penetrate into the brain [26]. Nanoparticles
interact with amyloid proteins, glutamate ionotropic
receptors and neuronal membrane. Therefore it is of
great interest to investigate the influence of fullerenes
introduced into the brain on the behavior and cogni
tive processes in the norm and on the models of brain
pathology. A single intraventricular (i/v) administra
tion of carboxyfullerene at a high concentration
1.6
−
30
1.4
1.2
1.0
0.8
0.6
0.4
−
20
−
100 10203040506070
C
60
FWS, 7
⋅
10
−
5
mg/mL
2
1
1
2
Time, min
@
HF stimulation
*
*
PS amplitude, arb. un.
Fig. 2.
Dynamics of the change in the amplitude of the population spike (PS) (normalized values) in control (
1
) and under the
action of C
60
FWS (
2
). Shown are the mean value ± standard error (
n
= 4). The insets present examples of PS before and after
highfrequency (HF) stimulation. The line shows the time of C
60
FWS introduction. *Significant difference from control before
and after HF stimulation,
p
< 0.05 [21].
74
BIOPHYSICS Vol. 55 No. 1 2010
PODOLSKI et al.
(4.5 mM in 20
μ
L) did not cause a disturbance in rat
behavior. An increase of the concentration by three
times led to convulsions and death [27]. Introduction
of fullerene into lateral ventricles of the brain
increased the locomotor activity and elevated the rate
of turnover of neuromodulators (serotonin and
dopamine) in brain structures. In distinction from
this, intravenous administration of fullerene did not
cause such action. This is explained by that the
fullerene poorly penetrates through the blood–brain
barrier [28]. We showed that a single administration of
fullerene into brain ventricles and hippocampus did
not disturb cognitive processes (Fig. 3) [16, 17]. On
the basis of these data it can be concluded that a single
introduction of fullerenes into the brain does not cause
acute neurotoxic action. However, this is only the very
beginning of investigations. It is important to investi
gate in detail how the brain is influenced by chronic
administration of various compounds of fullerenes. We
have for the first time studied the influence of fullerene
on the disturbance of memory in animals caused by
deep suppression of protein synthesis in the brain.
Suppression of protein synthesis is a classical model of
disturbance of formation of longterm memory [31].
The hippocampus plays a key role in memorizing
events, facts, space and time [32]. We found that intra
hippocampal microinjection of a complex of C
60
with
polyvinyl pyrrolidone (C
60
/PVP) prevented the distur
bance of spatial memory in rats caused by a high con
centration of cycloheximide, a blocker of protein
translation (Fig. 4) [29, 30]. The mechanism of this
effect is unknown. According to a computer model,
fullerene can absorb cycloheximide, decrease the sup
pression of protein synthesis and as a result of this pre
vent memory disturbances [33]. However, other expla
nations are also possible. We have planned conduction
of experimental investigations of the mechanisms of
this interesting effect.
According to our preliminary data, intraventricular
introduction of C
60
FWS restituted protein synthesis in
the pyramidal neurons of the hippocampus in 20% of
rats and weakened the disturbance of spatial memory
caused by introduction of A
β
25–35
[17].
The investigation of the influence of nanoparticles
on the disturbance of cognitive processes has recently
found further development. Chronic peroral adminis
tration of an antioxidant carboxyfullerene, which acts
as a mimetic of superoxide dismutase, significantly
weakened the oxidative stress, prevented the distur
bance of spatial memory in old mice and increased
their life duration [34].
We suppose than in the nearest years the investiga
tion of fullerene action on behavior and cognitive pro
cesses will find great development [35].
100
2
75
50
25
01 3 4
Seance no..
Latent period, s
3
1
2
Fig. 3.
Influence of microinjection of C
60
FWS into lateral
ventricles of the brain on cognitive processes (rapid forma
tion of spatial memory at random position of invisible tar
get) [16]. Latent period, the time of solving a probabilistic
spatial problem. Fullerene at concentration of 3.6 and
7.2 nmol/20
μ
L/ventricle (curves
1
and
2
corespectively)
did not disturb spatial learning and solving the probabilis
tic spatial problem; control, 0.9% solution of NaCl
20
μ
L/ventricle (curve
3
). Five tests in each shance.
300
2
150
100
50
01 3 4
Test no..
Latent period, s
5 6
250
200
(a)
2
1
2
150
100
50
03 4
Test no..
5 6
250
200
2
1
(b)
1
Fig. 4.
Influence of bilateral intrahippocampal microinjec
tion of PVP (a) and fullerene (C
60
/PVP) (b) on spatial
memory disturbed by intraventricular introduction of
cycloheximide, inhibitor of protein translation. Experi
ments performed in a Morris aquatic labyrinth. Training
conducted in one seance of 5 min duration consisting of six
tests (curve
1
). Checking the preservation of information
was performed by repeated learning after 24 h (curve
2
).
Cycloheximide (200
μ
g/20
μ
L/ventricle) disturbed the
preservation of information (nor shown). It is seen that
PVP did not prevent amnesia caused by cycloheximide (a),
C
60
/PVP at a concentration of 1.7
μ
g/1
μ
L/hemisphere
completely abolished it (b) [29].
BIOPHYSICS Vol. 55 No. 1 2010
FULLERENES C
60
, ANTIAMYLOID ACTION, THE BRAIN 75
DEVELOPMENT OF FULLERENEBASED
DRUGS FOR THERAPY OF THE EARLY STAGE
OF ALZHEIMER’S DISEASE
Alzheimer’s disease is a primary neurodegenerative
disease of people of advanced and old age. It afflicts
more than 24 million people in the world. This disease
is characterized by steady deterioration of memory up
to complete disintegration of intelligence and psychic
activity. The neurotoxic action of soluble A
β
42/43
oli
gomers and their fibrils leads toward death the syn
apses and neurons in the hippocampus, neocortex and
other parts of the brain [36, 37]. Modern drugs tempo
rarily improve the memory and weaken the dementia.
However, there are no means that can stop or cause a
reverse development of the destructive neurodegener
ative process. Development of antiamyloid drugs rep
resents one of the most active directions in the therapy
of Alzheimer’s disease [36, 37].
A promising field of investigations has appeared—
development on the basis of nanotechnology of drugs
for treating neurodegenerative diseases [10, 16, 17, 39,
40, 43]. An important problem is penetration of nano
particles through the blood–brain barrier. Recently
synthesis has been realized for carbon nanomaterials
penetrating the blood–brain barrier. Clinical trials of
these compounds are conducted [39].
In the literature it is customary to explain the neu
roprotector action of fullerene by its ability to quench
oxygen radicals and cause antioxidant action [5, 8, 10,
40]. International pharmaceutical companies such as
C. Sixty and Merck Co., using fullerenes, develop
antioxidants for therapy of neurodegenerative dis
eases, including AD [40]. However fullerenes are mol
ecules of multipurpose action, and this significantly
expands their possible application in medicine [41].
Our data have allowed a suggestion that
β
amyloids
and amyloid proteins represent a molecular target of
the action of fullerenes C
60
. Investigations of the anti
amyloid action of fullerenes may lead to development
of a new direction in AD therapy [11–18]. Owing to
the combination of antioxidant and antiaggregation
activity, fullerenes may prove helpful also in the devel
opment of neuroprotective drugs for therapy of neuro
degenerative diseases.
Of interest is one more kind of fullerene activity.
Derivatives of fullerenes are inhibitors of the aspartyl
protease of the AIDS virus [2, 4]. The
β
and
γ
secre
tases, as a result of the activity of which A
β
42/43
is
formed, belong to the group of aspartyl proteases,
apparently universal for various cellular systems and
organisms [37]. The question of whether fullerenes
inhibit
γ
secretase remains open.
CONCLUSIONS
The interdisciplinary investigation of the action of
fullerenes on molecular and cellular mechanisms of
neurodegenerative diseases and disturbance of cogni
tive processes is a new fundamental problem of neuro
science, nanobiotechnology and nanomedicine. Fur
ther study of the antiamyloid ability of fullerenes will
make a substantial contribution into the understand
ing of the mechanisms of their neuroprotector action
and influence on the disturbances of cognitive pro
cesses. These investigations present great interest for
constructing nanodrugs for therapy of the early stage
of AD and other neurodegenerative diseases. It is prin
cipally important that in Russia conditions be created
for investigation of the neuro and psychotropic activ
ity of fullerenes and development of therapy of neuro
degenerative diseases on their basis.
ACKNOWLEDGMENTS
The authors thank E. Makarova, L. Marsagishvili,
M.D. Shpagina, O. Kordonets, and E. Mugantseva for
collaboration and help in preparing the paper.
The work was supported by the RF Ministry of
Education and Science grant no. 2.1.1./3876.
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