ArticlePDF AvailableLiterature Review

Fullerenes C60, antiamyloid action, the brain, and cognitive processes

Authors:

Abstract and Figures

A short review of investigations along a new line: the antiamyloid action of fullerenes C60 and correction 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 wordsfullerenes C60 -antiamyloid action-neuron-memory-Alzheimer’s disease-neurodegenerative diseases
Content may be subject to copyright.
ISSN 00063509, 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 bpeptide; FWS, colloidal water suspension of
fullerene; AD, Alzheimer’s disease; NMDA, NmethylD
aspartate; AMPA, aamino3hydroxy5methyl4isoxazole
propionic acid; LTP, longterm 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
Email: 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 peptideformed 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 Xprotein 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 watersoluble derivatives. It
appears that hydrophobic interactions of fullerenes
with amyloid
β
peptides and Xprotein 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: NmethylDaspartate (NMDA),
α
amino3
hydroxy5methyl4isoxazole 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 potentialdependent 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 potentialdependent 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
highfrequency (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 longterm 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 FULLERENEBASED
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.
REFERENCES
1. H. Kroto, Usp. Fiz. Nauk
168
(3), 343 (1998).
2. A. B. Piotrovskii and O. I. Kiselev,
Fullerenes in Biology
(Rostok, St. Petersburg, 2006) [in Russian].
3. L. B. Piotrovskii, Ros. Nanotekhnol.
2
(7–8), 6 (2007).
4. R. Bakry, R. M. Vallant, M. NajamulHaq, et al., Int.
J. Nanomed.
2
, 639 (2007).
5. Z. Markovic and V. Trajkovic, Biomaterials
29
(26),
3561 (2008).
6. R. Qiao, A. P. Roberts, A. S. Mount, et al., Nano Lett.
7
(3), 614 (2007).
7. D. Bedrov, G. D. Smith, H. Davande, and L. Li,
J. Phys. Chem. B.
112
(7), 2078 (2008).
8. G. A. Silva, Nat. Rev. Neurosci.
7
(1), 65 (2006).
9. G. A. Silva, Nat. Nanotechnol.
4
(2), 82 (2009).
10. L. L. Dugan, D. M. Turetsky, C. Du, et al., Proc. Natl.
Acad. Sci. USA
94
, 9434 (1997).
11. A. S. Pai, I. Rubinstein, and H. Onyüksel, Peptides
27
(11), 2858 (2006).
12. W. H. Wu, X. Sun, and Y. P. Yu, Biochem. Biophys.
Res. Commun.
373
(2), 315 (2008).
13. I. Lynch and K. A. Dawson, Nanotoday
3
(1–2), 40
(2008).
14. E. Hellstrand, I. Lynch, A. Andersson, et al., FEBS J.
276
(12), 3372 (2009).
15. J. E. Kim and M. Lee, Biochem. Biophys. Res. Com
mun.
303
(2), 576 (2003).
16. I. Y. Podolski, Z. A. Podlubnaya, et al., J. Nanosci.
Nanotechnol.
7
(45), 1479 (2007).
17. I. Ya. Podolski, E. G. Makarova, E. A. Mugantseva,
et al., Nanotechnol. Int. Forum RUSNANO
2
, 221
(2008).
18. L. G. Marsagishvili, A. G. Bobylev, M.D. Shpagina,
et al., Biofizika
54
(2), 202 (2009).
19. H. Jin, W. Q. Chen, X. W. Tang, et al., J. Neurosci. Res.
62
(4), 600 (2000).
1
76
BIOPHYSICS Vol. 55 No. 1 2010
PODOLSKI et al.
20. G. V. Andrievsky, V. K. Klochkov, A. B. Bordyuh, et al.,
Phys. Lett.
364
, 8 (2002).
21. O. L. Kordonets, O. V. Godukhin, I. Ya. Podolski, and
L. M. Chailakhyan, Dokl. RAN
423
(5), 697(2008).
22. M. R. Bennett, Progr. Neurobiol.
60
, 109 (2000).
23. A. Atlante, P. Calissano, A. Bobba, et al., FEBS Lett.
497
(1), 1 (2001).
24. M.C. Tsai, Y. H. Chen, and L. Y Chiang, J. Pharm.
Pharmacol.
49
, 438 (1997).
25. H.M. Huang, H.C. Ou, S.J. Hsieh, and L.Y. Chiang,
Life Sci.
66
, 1525 (2000).
26. G. Oberdörster, Z. Sharp, V. Atudorei, et al., Inhal.
To x i c o l .
16
(67), 437 (2004).
27. A. M.Y. Lin, S.F. Fang, S.Z. Lin, et al., Neurosci.
Res.
43
(4), 317(2002).
28. T. Yamada, D. Y. Jung, R. Sawada, et al., J. Nanosci.
Nanotechnol.
8
(8), 3973 (2008).
29. I. Y. Podolski, E. V. Kondratjeva, I. V. Shcheglov, et al.,
Phys. Solid State
44
, 578 (2002).
30. I. Y. Podolski, E. V. Kondratjeva, S. S Gurin, et al.,
Fullerenes, Nanotubes, Carbon Nanostructures
12
,
443 (2004).
31. P. J. Hernandez and T. Abel, Neurobiol. Learn. Mem.
89
(3), 293 (2008).
32. G. Neves, S. F. Cooke, and T. V. Bliss, Nat. Rev. Neu
rosci.
9
(1), 65 (2008).
33. I. V. Zaporotskova and L. A. Chernozatonskii,
Fullerenes and Atomic Clusters IWFAC Abstract 201
(2003).
34. K. L.Quick, S. S. Ali, R. Arch, et al., Neurobiol. Aging
29
(1) 11 (2008).
35. I. Ya. Podolski, in educational video “Neuron and
Memory,” Ed.by F. A. Filippov and A. M. Chernorizov
(2009), http://www.eurasion.ru.
36. D. J. Selkoe, Nutr. Rev.
65
(12 Pt 2), 239 (2007).
37. A. P. Grigorenko and E. I. Rogaev, Mol. Biol.
41
,
331(2007).
38. D. M. Walsh and D. J. Selkoe, J. Neurochem.
101
,
1172 (2007).
39. L. J. Gilmore, Yi. Xiang, Q. Lingdong, and
A. V. Kabanov, J. Neuroimm. Pharmacol.
3
(2), 83
(2008).
40. S. S. Ali, J. I. Hardt, and L. L. Dugan, Nanomedicine
4
(4), 283 (2008).
41.
Small times magazine
July 20 (2007), http://www.elec
troiq.com/index/nanotechmems/stcurrent
issue/smalltimes/volume7/issue4.html.
42. A. MateoAlonso, D. M Guldi, F. Paolucci, and
M. Prato, Angew. Chem. Int. Ed. Engl.
46
(43), 8120
(2007).
43. A. S. Basso, et al., J. Clin. Invest.
118
(4), 1532 (2008).
SPELL: 1. ok
... Water-soluble fullerene has been reported to be able to absorb free radicals, promote skeletal muscle regeneration (Ishii et al. 2013;Ishii et al. 2014), and inhibit arthritis (Yudoh et al. 2009b;Yudoh et al. 2009a). Podolski and co-workers conducted extensive studies on the anti-amyloid effect of fullerene and its potentials in treating Alzheimer's disease, in the aspects of reversing cognition impairment, preventing neurodegeneration and protecting neuroplasticity (Gordon et al. 2017;Makarova et al. 2012;Podlubnaya et al. 2006;Podolski et al. 2010;Podolski et al. 2007;Vorobyov et al. 2015). ...
... b-e Relative levels of protein (PSD-95, SYP, BDNF, and TrkB, respectively) in mouse hippocampus. Data were presented as mean ± SEM. *p < 0.05 (Gordon et al. 2017;Makarova et al. 2012;Podlubnaya et al. 2006;Podolski et al. 2010;Podolski et al. 2007;Vorobyov et al. 2015). Podolski and co-workers demonstrated that the anti-amyloid effect of hydrated fullerene could reverse the impairment of cognitive performance of rats induced by Aβ 25-35 injection (Gordon et al. 2017;Podolski et al. 2007), probably through inhibiting the fibrillization of Aβ 25-35 peptide (Podolski et al. 2007). ...
Article
Full-text available
Fullerene is a family of carbon materials widely applied in modern medicine and ecosystem de-contamination. Its wide application makes human bodies more and more constantly exposed to fullerene particles. Since fullerene particles are able to cross the blood-brain barrier (BBB) (Yamago et al. 1995), if and how fullerene would affect brain functions need to be investigated for human health consideration. For this purpose, we administered fullerene on subcortical ischemic vascular dementia (SIVD) model mice and sham mice, two types of mice with distinct penetration properties of BBB and hence possibly distinct vulnerabilities to fullerene. We studied the spatial learning and memory abilities of mice with Morris water maze (MWM) and the neuroplasticity properties of the hippocampus. Results showed that fullerene administration suppressed outcomes of MWM in sham mice, along with suppressed long-term potentiation (LTP) and dendritic spine densities. Oppositely, recoveries of MWM outcomes and neuroplasticity properties were observed in fullerene-treated SIVD mice. To further clarify the mechanism of the impact of fullerene on neuroplasticity, we measured the levels of postsynaptic density protein 95 (PSD-95), synaptophysin (SYP), brain-derived neurotrophic factor (BDNF), and tropomyosin receptor kinase B (TrkB) by western blot assay. Results suggest that the distinct impacts of fullerene on behavior test and neuroplasticity may be conducted through postsynaptic regulations that were mediated by BDNF.
... Fluorescent NDs, when intracranial injected, induced neurite outgrowth but also caused a dose-dependent decline in neurite length in both PNS and CNS neurons. Table 2 depicts the outcomes of carbon nanostructures on CNS [63][64][65][66][67][68][69][70][71][72][73][74][75]. 16 ...
Article
Drug delivery through the blood-brain barrier (BBB) is one of the key challenges in the modern era of medicine due to the highly semipermeable characteristics of BBB that restrict the entry of various drugs into the central nervous system (CNS) for the management of brain disorders. Drugs can be easily incorporated into carbon nanocarriers that can cross the bloodbrain barrier. Numerous nanocarriers have been developed, including polymeric nanoparticles, carbon nanoparticles, lipid-based nanoparticles, etc. Among these, carbon nanostructures could be superior due to their easier BBB penetration and strong biocompatibility. Several CDs (Carbon dots) and CD-ligand conjugates have explored effectively penetrating the BBB, which enables significant progress in using CD-based drug delivery systems (DDS) to manage CNS diseases. Despite the drug delivery applications, they might also be used as a central nervous system (CNS) drug; few of the carbon nanostructures show profound neurodegenerative activity. Further, their impact on neuronal growth and anti- amyloid action is quite interesting. The present study covers diverse carbon nanostructures for brain-targeted drug delivery, exploring a variety of CNS activities. Moreover, it emphasizes recent patents on carbon nanostructures for CNS disorders.
... The fullerene absorbing properties of reactive oxygen/nitrogen species generated by the overexcitation of glutamic acid receptors can be exploited to protect from neurodegenerative diseases like Alzheimer's and Parkinson's diseases [436]. The unpaired antioxidant activity of fullerenes is used to reduce the apoptosis in cortical neurons and to block the receptors of glutamic acid which are accompanied by antiamyloid action [437]. The same antioxidant activity of fullerenes is exploited in cosmetics to decrease inflammatory lesions and to protect against ultraviolet absorption leading to oxidative cell stress and aging [438]. ...
Article
Full-text available
Over the past decade, carbon nanostructures (CNSs) have been widely used in a variety of biomedical applications. Examples are the use of CNSs for drug and protein delivery or in tools to locally dispense nucleic acids to fight tumor affections. CNSs were successfully utilized in diagnostics and in noninvasive and highly sensitive imaging devices thanks to their optical properties in the near infrared region. However, biomedical applications require a complete biocompatibility to avoid adverse reactions of the immune system and CNSs potentials for biodegradability. Water is one of the main constituents of the living matter. Unfortunately, one of the disadvantages of CNSs is their poor solubility. Surface functionalization of CNSs is commonly utilized as an efficient solution to both tune the surface wettability of CNSs and impart biocompatible properties. Grafting functional groups onto the CNSs surface consists in bonding the desired chemical species on the carbon nanoparticles via wet or dry processes leading to the formation of a stable interaction. This latter may be of different nature as the van Der Waals, the electrostatic or the covalent, the π-π interaction, the hydrogen bond etc. depending on the process and on the functional molecule at play. Grafting is utilized for multiple purposes including bonding mimetic agents such as polyethylene glycol, drug/protein adsorption, attaching nanostructures to increase the CNSs opacity to selected wavelengths or provide magnetic properties. This makes the CNSs a very versatile tool for a broad selection of applications as medicinal biochips, new high-performance platforms for magnetic resonance (MR), photothermal therapy, molecular imaging, tissue engineering, and neuroscience. The scope of this work is to highlight up-to-date using of the functionalized carbon materials such as graphene, carbon fibers, carbon nanotubes, fullerene and nanodiamonds in biomedical applications.
... We aimed to understand the influence of these compounds on pi-pi stacking interactions using compounds like polyphenols, 7 non-steroidal anti-inflammatory drugs (NSAID's), 8 coumarin, 9 cinnamaldehyde 10 and fullerene. 11 We also studied the interaction of the anti-amyloid host-guest inclusion compounds like cyclodextrin 12 and cucurbituril 13 with FF. Our investigations reveal that the known anti-amyloid compounds indeed caused disruption of FF fibers consistent with the reductionist approach proposed by Gazit and coworkers. ...
Preprint
Full-text available
Aggregation of amyloid beeta 1-42 (Aβ42) peptide causes the formation of clustered deposits knows as amyloid plaques in the brain which leads to neuronal dysfunction and memory loss and associated with many neurological disorders including Alzheimer’s and Parkinson’s. Aβ42 has core structural motif with phenylalanine at the 19 and 20 positions. The diphenylalanine (FF) residue plays a crucial role in the formation of amyloid fibers and serves as model peptide for studying Aβ42 aggregation. FF self-assembles to well-ordered tubular morphology via aromatic pi-pi stackings. Our studies, suggest that the aromatic rings present in the anti-amyloidogenic compounds may interact with the pi-pi stacking interactions present in the FF. Even the compounds which do not have aromatic rings, like cyclodextrin and cucurbituril show anti-amyloid property due to the binding of aromatic ring inside the guest cavity. Hence, our studies also suggest that compounds which may have a functional moiety capable of interacting with the aromatic stacking interactions might be tested for their anti-amyloidogenic properties. Further, in this manuscript, we have proposed two novel nanoparticle based assays for the rapid screening of amyloid inhibitors. In the first assay, interaction between biotin-tagged FF peptide and the streptavidin labelled gold nanoparticles (s-AuNPs) were used. In another assay, thiol-Au interactions were used to develop an assay for detection of amyloid inhibitors. It is envisaged that the proposed analytical method will provide a simple, facile and cost effective technique for the screening of amyloid inhibitors and may be of immense practical implications to find the therapeutic remedies for the diseases associated with the protein aggregation.
Article
Full-text available
Such carbon structures as fullerenes, endofullerenes, nanotubes, nanodiamonds, and graphenes, which were discovered over recent decades, possess a number of unique properties and can become the basis for the design of a new class of neuroprotective agents; however, despite years of research, this has not happened yet. In the first part of the review, the significance of the functionalization of carbon nanoparticles for their use in biology and medicine is described, and the data on their toxicity are also discussed. The second part presents the works of Russian and foreign scientists demonstrating the neuroprotective properties of carbon nanoparticles and the possibilities of their application in neurobiology and neurology. The successful experience of such experiments is described and the existing problems are indicated.
Article
The open border between non-living and living matter, suggested by increasingly emerging fields of nanoscience interfaced to biological systems, requires a detailed knowledge of nanomaterials properties. An account of the wide spectrum of phenomena, belonging to physical chemistry of interfaces, materials science, solid state physics at the nanoscale and bioelectrochemistry, thus is acquainted for a comprehensive application of carbon nanotubes interphased with neuron cells. This review points out a number of conceptual tools to further address the ongoing advances in coupling neuronal networks with (carbon) nanotube meshworks, and to deepen the basic issues that govern a biological cell or tissue interacting with a nanomaterial. Emphasis is given here to the properties and roles of carbon nanotube systems at relevant spatiotemporal scales of individual molecules, junctions and molecular layers, as well as to the point of view of a condensed matter or materials scientist. Carbon nanotube interactions with blood-brain barrier, drug delivery, biocompatibility and functionalization issues are also regarded.
Article
Neurodegenerative disorders and brain tumors are major pathological conditions affecting the brain. The delivery of therapeutic agents into the brain is not as easy as to other organs or systems. The presence of the blood-brain barrier (BBB) makes the drug delivery into the brain more complicated and challenging. Many techniques have been developed to overcome the difficulties with BBB and to achieve brain-targeted drug delivery. Incorporation of the drugs into nanocarriers capable to penetrate BBB is a simple technique. Different nanocarriers have been developed including polymeric nanoparticles, carbon nanoparticles, lipid-based nanoparticles, etc. Carbon nanostructures could make a superior position among them, because of their good biocompatibility and easy penetration of BBB. Carbon-family nanomaterials consist of different carbon-based structures including zero-dimensional fullerene, one-dimensional carbon nanotube, two-dimensional graphene, and some other related structures like carbon dots and nanodiamonds. They can be used as efficient carriers for drug delivery into the brain. Apart from the drug delivery applications, they can also be used as a central nervous system (CNS) therapeutic agent; some of the carbon nanostructures have neuroregenerative activity. Their influence on neuronal growth and anti-amyloid action is also interesting. This review focuses on different carbon nanostructures for brain-targeted drug delivery and their CNS activities. As a carrier and CNS therapeutic agent, carbon nanostructures can revolutionize the treatment of brain disorders.
Article
Background. C60 fullerenes and their derivatives are actively investigated for the use in neuroscience. Applications of these nanoscale materials require the examination of their interaction with different neural cells, especially with microglia, since these cells, like other tissue resident phagocytes, are earliest and most sensitive responders to nanoparticles. The aim of this study was to investigate the effect of C60 fullerene and its nanocomplex with doxorubicin (Dox) on metabolic profile of brain resident phagocytes – microglia – in vitro. Methods. Resting microglial cells from adult male Wistar rats were used in experiments. Potential C60 fullerene targets in microglial cells were studied by computer simulation. Microglia oxidative metabolism and phagocytic activity were examined by flow cytometry. Griess reaction and arginase activity colorimetric assay were used to explore arginine metabolism. Results. C60 fullerene used alone didn’t influence microglia oxidative metabolism and phagocytic activity, and shifted arginine metabolism towards the decrease of NO-generation. Complexation of C60 fullerene with Dox (C60-Dox) potentiated the ability of the latter to stimulate NO generation. Conclusion. The capability of C60 fullerenes used alone to cause anti-inflammatory shift of microglia arginine metabolism makes them a promising agent for the correction neuroinflammatory processes involved in neurodegeneration. Potentiating action of C60 fullerene on immunomodulatory effect of Dox allows to consider C60 molecule as attractive vehicle for this antitumor agent.
Article
Full-text available
Studies of the molecular mechanisms of Alzheimer’s disease (AD) have led to two major achievements. First, genes with mutations causing AD (PS1 and PS2 presenilin genes and APP) or bearing a risk factor polymorphism (APOE) have been described. Second, a new type of proteases has been identified along with the mechanisms regulating cell differentiation and development via intramembrane proteolysis. These mechanisms are apparently universal for various cell systems and organisms. Presenilin is a catalytic component of the tetraprotein complex (ɛ-/γ-secretase) that cleaves type I transmembrane proteins. Type II transmembrane proteins are cleaved by IMPAS/SPP aspartate proteases, found recently. The processing of transmembrane proteins by intramembrane proteases generates signal peptides, transcription factors, and short hydrophobic proteins (fragments of transmembrane domains), which can play both a physiological role and a key role in pathological events associated with aging (β-amyloid in AD). About 160 PS1 mutations, more than ten PS2 mutations, and 21 APP mutations have been described to date. Preclinical diagnosis has become possible for some early-onset forms of AD. Since early-and late-onset forms of AD are similar in pathogenesis, studies of proteolysis driven by intramembrane aspartate proteases may eventually contribute to the development of drugs directly affecting the processing of transmembrane proteins as a primary mechanism of AD.
Article
Full-text available
The inhibitory effect of hydrated fullerene C60 (HyFn) and the sodium salt of the fullerene polycarboxylic derivative C60Cl (C6H4CH2COONa)5 on the formation of amyloid fibrils by X-protein in vitro has been studied by electron microscopy. It has been shown that these compounds not only destroyed mature amyloid fibrils but also prevented the formation of new fibrils. This property of fullerenes, nanoparticles, can be used for the development of a novel medicinal nanotechnology in the therapy of amyloidoses.
Article
Full-text available
New insights are emerging about the interactions between brain cells and carbon nanotubes, which could eventually lead to the development of nanoengineered neural devices.
Article
We report that fullerene inhibits strongly the amyloid peptide aggregation at the early stage. It specifically binds to the central hydrophobic motif, KLVFF, of Aβ peptides. The IC50 value has been measured as 9μM for both Aβ11–25 and Aβ1–40. On the other hand, a control experiment shows melatonin rather specifically binds to the C-terminus region. The IC50 value of fullerene appears to be at least four times larger for Aβ1–40, compared with melatonin, and 15 times larger for Aβ11–25. This work shows that fullerene can be a promising candidate in search of AD therapeutics because it has the very high IC50 value for Aβ aggregation.
Article
It is shown that fullerene C60/water‐soluble complex with PVP molecular mass of 10,000 injected in the dorsal hippocampus completely prevents the development of amnesia caused by cycloheximide, the inhibitor of protein synthesis. With the increased PVP molecular mass up to 25,000 the complex does not produce protective effect disturbance of learning.
Article
A microinjection of C60/poly-(N-vinyl-pyrrolidone) (C60/PVP) adduct into the dorsal hippocampus is shown to prevent the disturbance of spatial memory consolidation induced by the administration of a high dose of cycloheximide, which inhibits protein synthesis in the central nervous system by more than 90%. It is supposed that microinjections of the C60/PVP adduct into the hippocampus suppress the death of its neurons, which may be one of the essential factors that prevent the disturbance of long-term memory consolidation by protein-synthesis inhibition. Other mechanisms of the fullerene action are also possible; however, they remain as yet unknown.
Article
The key role of protein-nanoparticle interactions in nanomedicine and nanotoxicity has begun to emerge recently with the development of the idea of the nanoparticle-protein ‘corona’. This dynamic layer of proteins (and other biomolecules) adsorbs to nanoparticle surfaces immediately upon contact with living systems. While within the biomaterials field the role of adsorbed molecules in cellular responses is acknowledged, there are several new issues at stake where nanoparticles are concerned. We show here that highly selective protein adsorption, added to the fact that particles can reach subcellular locations, results in significant new potential impacts for nanoparticles on protein interactions and cellular behavior.
Article
Superoxide radical anion is a biologically important oxidant that has been linked to tissue injury and inflammation in several diseases. Here we carried out a structure-activity study on six different carboxyfullerene superoxide dismutase (SOD) mimetics with distinct electronic and biophysical characteristics. Neurotoxicity via N-methyl-D-aspartate receptors, which involves intracellular superoxide, was used as a model to evaluate structure-activity relationships between reactivity toward superoxide and neuronal rescue by these drugs. A significant correlation between neuroprotection by carboxyfullerenes and their ki toward superoxide radical was observed. Computer-assisted molecular modeling demonstrated that the reactivity toward superoxide is sensitive to changes in dipole moment, which are dictated not only by the number of carboxyl groups but also by their distribution on the fullerene ball. These results indicate that the SOD activity of these cell-permeable compounds predicts neuroprotection, and establishes a structure-activity relationship to aid in future studies on the biology of superoxide across disciplines.
Article
In a biological environment, nanoparticles immediately become covered by an evolving corona of biomolecules, which gives a biological identity to the nanoparticle and determines its biological impact and fate. Previous efforts at describing the corona have concerned only its protein content. Here, for the first time, we show, using size exclusion chromatography, NMR, and pull-down experiments, that copolymer nanoparticles bind cholesterol, triglycerides and phospholipids from human plasma, and that the binding reaches saturation. The lipid and protein binding patterns correspond closely with the composition of high-density lipoprotein (HDL). By using fractionated lipoproteins, we show that HDL binds to copolymer nanoparticles with much higher specificity than other lipoproteins, probably mediated by apolipoprotein A-I. Together with the previously identified protein binding patterns in the corona, our results imply that copolymer nanoparticles bind complete HDL complexes, and may be recognized by living systems as HDL complexes, opening up these transport pathways to nanoparticles. Apolipoproteins have been identified as binding to many other nanoparticles, suggesting that lipid and lipoprotein binding is a general feature of nanoparticles under physiological conditions.