DEPARTMENT OF NEUROCHEMISTRY
1.- Staff of the Neurochemistry Department:
| Federico Dajas | Professor, M. D.* |
| Gustavo Costa | Associate Researcher* |
| Associate Researcher* | |
| Andrés Abin, Chemist | Assistant Researcher* |
| Assistant Researcher* |
|
| Felicia Rivera , Msc. PhD | student (PEDECIBA)** |
| Margot Ferreira | Fellow ** |
| Jessika Urbanavicius | Fellow** |
| Florencia Arredondo | Fellow ** |
| Andrea Morquio | Fellow** |
* Permanent
positions
** Positions
supported by grants
2.- Summary of the research
projects of the Neurochemistry Department
2.1.-
Neuronal plasticity in the rat
striatum
The overall goal of this Project is to increase understanding
of the nicotinic modulation of striatal dopamine release and the plastic mechanisms
underlying nicotinic receptor-mediated neuroprotection, by identifying and
exploiting new nicotinic ligands. This Project brings together a range of
complementary expertise, comprising:
·
chemistry for
the synthesis of novel ligands for nicotinic acetylcholine receptor (nAChR)
subtypes (DrB. Cassels, Santiag, Chile ),
·
oocyte electrophysiology
for evaluation of their subtype-selective activities at nAChR (Dr I. Bermudez, Oxford, UK),
·
molecular modelling
of ligands to determine the structural basis for their selectivity (DrM. Ortells,
collaborator, Buenos Aires),
·
in
vitro neurochemistry to exploit the ligands
to characterise the nicotinic modulation of dopamine release (Prof. S. Wonnacott, Bath, UK),
·
in
vivo neurochemical studies to
assess the neuroprotective potential of novel ligands and underlying mechanisms
of neuroprotection in a lesion model relevant to Parkinson’s disease (Dr F. Dajas, Montevideo).
Neuronal nAChR are a family
of ligand-gated ion channel (LGIC) receptors expressed in the central and
peripheral nervous systems and responsive to the neurotransmitter acetylcholine
(ACh). These receptors have attracted the interest as targets for therapeutic
intervention in a number of diverse conditions, including neurodegenerative
diseases, schizophrenia, epilepsy, anxiety and attention deficit disorder.
Of
these conditions, the positive relationship between nAChR and Parkinson’s
disease (PD) is perhaps the most robust: it stems from well corroborated epidemiological
studies showing a negative correlation between tobacco smoking and the incidence
of PD. Research carried out in the Neurochemistry Department of the Clemente
Estable Institute has shown that an intermittent treatment schedule of nicotine significantly prevented
the DA loss.
We hypothesise that stimulation
of nAChR delays the degeneration of
DAergic axons. This model,
in which an intermittent nAChR agonist stimulation significantly slows the
loss of DA in the striatal terminal fields
corresponds to a therapeutic window in the less aggressive progression
of clinical PD, when a significant retardation of the neurodegeneration might
be elicited through nicotinic cholinergic stimulation. The understanding
of the dynamics of striatal plasticity, and the characterization and exploitation
of novel nAChR agonists able to modulate striatal function is the ultimate
aim of this research.
2.2.- Neuroprotective
South American medicinal plants
With
the prolongation of the life span due to advancement of technology, brain
pathology is increasingly gaining importance all over the world. Together,
degenerative diseases of the nervous system affect more than 10% of the population
over 65 years. Given this high prevalence, the search for new therapeutics
is a scientific activity with great economic and social potential.. Nature
is a rich source of new molecules and a great number of therapeutics now in
use has their roots in natural products. The flora and fauna of South America is one
of the greatest in the world in the number of species, representing a still
poorly explored richness. Biodiversity
is thus the most important natural resource available for South American countries,
a resource whose potential for sustainable development is a challenge to be
addressed at the national and international level.
The research strategy of the Neurochemistry Division
aims at exploring the plant biodiversity of South America for activities in
the central nervous system, mainly the potential for treating diseases like
Parkinson Disease and Alzheimer´s Dementia. Since oxidative stress with its
concomitant overproduction of free radicals is involved in the etiology of
neurodegenerative diseases, natural compounds can be a source of lead molecules
for antioxidant activity.
Results
already obtained have shown that :
a) Achyrocline
satureioides (Lam.) DC. (Asteraceae),
(AS) has potent antioxidant capacity and a marked cyto and neuroprotective
activity for cells in culture.
b)
Haplopappus multifolius, (HM) a Chilean
plant sharing flavonoid composition
with AS has also shown strong antioxidant
and cytoprotective activity for cells in culture.
Accordingly with these findings, it has been hypothesized
that flavonoid aglycones of a particular group, structurally related to quercetin,
likely acting synergistically with other plant compounds, are responsible
for the cytoprotective activity of AS and HM and
are the basis for neuroprotection in vivo.
Thus, present research activities aim at providing
evidence of the capacity of phytochemically characterized extracts and flavonoid
fraction of AS and HM to revert brain experimental ischemic lesions in
vivo. To advance in the comprehension of the mechanisms involved, the
oxidized/reduced glutathione ratio is currently assessed, as an indicator
of the importance of redox equilibrium for cell survival. The blockade of
the DNA breakage of neurons is also studied to understand the mechanisms through
which active plant fractions might interfere cell death process.
3.-
Papers in peer reviewed journals period
2.- Evidences for a non-cholinergic function of acetylcholinesterase during development of chicken retina as shown by fasciculin. Blasina MF, Faria AC, Gardino PF, Hokoc JN, Almeida OMMS, Mello FG, Arrut C., Dajas F. Cell and Tissue Res 299:173-184.
3.- Do structural deviations between toxins adopting the same fold reflect functional differences ? Ricciardi A, le Du MH, Khayati M, Dajas F, Boulain JC, Menez A, Ducancel F. Jr. Biol. Chem 275:18302-18310.
4.- Nicotine prevents striatal dopamine loss produced by 6-hydroxydopamine lesion in the substantia nigra. Costa G, Abin JA, Dajas F. Brain Res 888:336-342.
5.- Intracerebral administration of 2,4-Dichloro-phenoxyacetic acid induces behavioral and neurochemical alterations in the rat brain. Bertolozzi A, Evangelista de Duffard AM, Dajas F., Duffard R.,Silveira R. Neurotoxicology 22:221-232.
6.-
Presynaptic involvement in the nicotine prevention of the dopamine loss provoked
by 6-OHDA administration in the substantia nigra
Abin Carriquiry JA, McGregor R, Costa G., Urbanavicius J, Dajas F. Neurotoxicity
Res. 4 , 133-139.
7.-Neuroprotection by cholinergic and antioxidant mechanisms in experimental parkinsonism F. Dajas, G. Costa, A. Abin. Functional Neurology 17, 37-44.
8.- Screening of antioxidant activity of three Indian medicinal plants, traditionally used for the management of neurodegenerative diseases. B.Auddy , M.Ferreira , F.Blasina , L. Lafon, F.Arredondo , F.Dajas, P.C.Tripathi and B.Mukherjee. Jr. of Ethnopharmacol. , 84, 131-138.
9.- Neuroprotection by flavonoids Dajas F, Rivera F, Blasina F, Arredondo F, Abin A, Costa G, Echeverry C, Lafon L, Heizen H, Ferreira M, Morquio A. Braz J Med Biol Res 36 , 1613-1620.
10.- Cell Culture Protection and in vivo Neuroprotective Capacity of Flavonoids Dajas Federico, Rivera Felicia, Blasina Fernanda, Arredondo Florencia, Echeverry Carolina, Lafon Laura, Morquio Andrea and Heinzen Horacio Neurotoxicty Res 5, 377.384.
11.- Cytoprotection by Achyrocline satureoides (Lam) D.C. and some of its main flavonoids against oxidative stress. Arredondo F, Blasina F, Echeverry C, Morquio A, Ferrerira M, Abin JA, Lafon L, Dajas F. Jr. thnopharmacol.
1.
Tests paraclínicos para el diagnóstico
del déficit atencional.
Bailador
P., Dajas F.
Revista de Psiquiatría del Uruguay,
62:23-30
2.- Alta tasa de suicidio en Uruguay,
IV: La situación epidemiológica actual.
Revista Médica
del Uruguay 17:
24.32,
3.- Producción de radicales hidroxilo
en sangre de pacientes ancianos
Dajas F., Martínez A., Ferrari
A., Ferreira M., Zeppi M., Pintos A.
Revista Médica del Uruguay
4.- Support for research projects.
“Regulation of the nicotinic acetylcholine receptor and
neurorpotection” Clemente Estable Fund, Project N 4001,
“Characterization of antioxidant compounds from natural
products”
Grinlab
SA 2001;
Antioxidant activity in brown algae. Isolation, pharmacological
and toxicity studies.”
International
Foundation for Science (IFS F/2838-1),
“Capacity of 2,4 di chloro acetic acid as an endocrine
disruptor” (in collaboration with the
University of Rosario, Argentine)
RELAB
OPS, Collaborative projects between Latin American and Caribbeand Laboratories.
“Neuronal plasticity in the rat striatum”
Wellcome
Trust, UK, 2003-2006
5.-
Teaching activities
a)
International
postgraduate teaching course attended by students from the region (Brazil,
Argentine, Chile, Peru, etc) and given by Professors from the region (South
America), Europe and USA.
b)
Regular
training of master and PhD students.
At present, 2 PhD students, 2 Msc students.
6.- Conferences by invitation
Neuroprotection by cholinergic and antioxidant mechanisms
in experimental parkinsonism F. Dajas
Symposium: Parkinson´s Disease and other movement disorders,
Pavia, Italia.
Developing Natural Compounds that can protect the
brain
Dajas F., Costa G., Abin JA., Lafon L., Echeverry
C., Blasina F.
Asian Simposium on Medicinal Plants, spices and other Natural Products
Dhaka , Bangladesh
Mechanisms of nicotinic cholinergic neuroprotection in
experimental parkinsonism.
F. Dajas, JA Abin, G. Costa, R. McGregor, J. Urbanavicius.
Symposium: The decade of
the brain at the C. Mondino Foundation.
Pavia,Italia,
Has nicotine a protective role agaisnt 6-OHDA neurotoxicity
?
F.
Dajas, Juan A. Abin, Gustavo Costa
Neurotoxicity meeting: mechanisms for neurodegenerative
disorders,
Pucón, Chile, March 16-18, Abstracts pp. 15,
Dajas
F
Antioxidant and neuroprotection activities from natural
compounds:
Criteria for Biological Testing
Intercontinenetal
scientific quorum , Natural products. Addis Ababa, Ethiopia,
Dajas F.
Mechanisms of neuroprotection. The contribution of
quercetibn in focal ischemia and cell culture
XVII
Reuniao Anual da Federacao de Sociedades de Biologia Experimental (FESBE).
Salvador, Bahia.
7.-
Conferences, organized
First
International Symposium on Natural
Product Research in Three Continents
Montevideo, Supported by OPCW
(Organization for the Prohibition of Chemical Weapons).
8.-
Diagnostic Services
Assessment
of plsma and urinary catecholamines for the diagnosis of pheochromocitoma
and the evaluation of Stress and Attention Deficit Hyperactivity Disorder.
A service to the community regularly provided by the
Neurochemistry Dept. since more than 20 years ago, after original research
of the department on the procedures to assess catecholamines by HPLC with
electrovchemical detection.