vascularización cerebral (parte ii)

Angiogénesis y neurogénesis

Dos caminos paralelos

martes 15 de noviembre de 2011

“De humani corporis fabrica”


Carmeliet and Tessier-Lavigne, Nature. 2005


Zacchigna et al., Nature Reviews Neuroscience. 2008


Desarrollo cortical

Predeterminado genéticamente

Mediado por experiencia


Desarrollo cortical

Predeterminado genéticamente

Mediado por experiencia

PERIODO CRÍTICO3ª - 5ª semanas


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Neurogenesis Angiogenesis


Nicho vascular (neurogenesis). Palmer 2000.

Incremento demanda. Black 1987.

Coordinados. Carmeliet 2005.

Neurogenesis Angiogenesis


Desarrollo neurovascularEvento coordinado

Respuesta común a señales comunes

VEGF

Neurotrofinas (NGF, BDNF, NTs)

Neuropilinas (Nrp1, Nrp2)

Semaforinas (Sema3A)

Efrinas/Ephs (EphB-ephrinB)

Angiopoyetinas (Ang2)


ANGIOGENESIS BUT NOT NEUROGENESIS IS CRITICAL FORNORMAL LEARNING AND MEMORY ACQUISITION

A. L. KERR,1 E. L. STEUER, V. POCHTAREV ANDR. A. SWAIN*

University of Wisconsin-Milwaukee, Milwaukee, WI, USA

Abstract—Aerobic exercise has been well established to pro-mote enhanced learning and memory in both human andnon-human animals. Exercise regimens enhance blood per-fusion, neo-vascularization, and neurogenesis in nervoussystem structures associated with learning and memory. Theimpact of specific plastic changes to learning and memoryperformance in exercising animals are not well understood.The current experiment was designed to investigate the con-tributions of angiogenesis and neurogenesis to learning andmemory performance by pharmacologically blocking eachprocess in separate groups of exercising animals prior tovisual spatial memory assessment. Results from our experi-ment indicate that angiogenesis is an important componentof learning as animals receiving an angiogenesis inhibitorexhibit retarded Morris water maze (MWM) acquisition. Inter-estingly, our results also revealed that neurogenesis inhibi-tion improves learning and memory performance in theMWM. Animals that received the neurogenesis inhibitor dis-played the best overall MWM performance. These resultspoint to the importance of vascular plasticity in learning andmemory function and provide empirical evidence to supportthe use of manipulations that enhance vascular plasticity toimprove cognitive function and protect against natural cog-nitive decline. © 2010 IBRO. Published by Elsevier Ltd. Allrights reserved.

Key words: vascular plasticity, exercise-induced facilitation,Morris water maze.

Aerobic exercise promotes enhanced learning and mem-ory in both human and non-human animals. At the cellularlevel, exercise is associated with increased angiogenesis(the sprouting of new capillaries from preexisting bloodvessels) and/or neurogenesis in various areas of the brainincluding the hippocampus, motor cortex and cerebellum(Black et al., 1991; Clark et al., 2009; Isaacs et al., 1992;Kim et al., 2002; Sikorski et al., 2008; Swain et al., 2003;van Praag et al., 2005). Aerobic exercise in rodents is alsoassociated with improved recovery following ischemic in-sult (Lee et al., 2003a,b; Sim et al., 2004) and improved

cognitive performance on a variety of tasks including theMorris water maze (MWM), contextual fear conditioning,extinction of contextual fear, and radial arm maze (Ander-son et al., 2000; Baruch et al., 2004; Fordyce and Wehner,1993; Gobbo and O’Mara, 2004; Pietropaolo et al., 2006;Powell, 2005; Vaynman et al., 2004). In humans, exercisehas been associated with improved cognitive performance inyoung adult, aging adult, and brain-injured populations(Churchill et al., 2002; Grealy et al., 1999; Kramer and Erick-son, 2007; Kramer et al., 2006; Winter et al., 2007) and hasbeen shown to protect against the onset of various demen-tias, including Alzheimer’s disease (Laurin et al., 2001).

The means by which experience facilitates learningand memory are not fully understood. However, the sur-vival of new neurons may contribute to learning and mem-ory changes following exercise. It has been consistentlyshown that both enriched environments and exercise (vol-untary and forced) promote neurogenesis in the adult hip-pocampus, specifically in the dentate gyrus (DG) (Christieet al., 2008; Kempermannn et al., 1997, 1998; Kim et al.,2002; Olson et al., 2006; Uysal et al., 2005; Van der Borghtet al., 2006; van Praag et al., 2005), and exercise-inducedneurogenesis is correlated with improved learning and mem-ory performance (Uysal et al., 2005; van Praag et al., 2005).However, there are also reports that manipulation of neuro-genesis does not impact learning and memory function in theMWM (Meshi et al., 2006; Shors et al., 2002) or contextualfear conditioning (Clark et al., 2008; Shors et al., 2002),indicating that neurogenesis may not be the sole supporter ofenhanced cognitive performance following exercise.

The contribution of neurogenesis to learning and mem-ory function is further complicated by recent evidence sug-gesting that newly proliferated neurons are not immedi-ately and functionally incorporated into existing learningnetworks. While it is clear that new neurons do becomefunctionally integrated into the existing circuitry eventually,several recent reports indicate that this integration is asomewhat delayed process taking between 3 and 4 weeksto complete (Kee et al., 2007; Overstreet et al., 2004; vanPraag et al., 2002). These data are supported by behav-ioral studies indicating that impaired neurogenesis doesnot affect visual spatial memory in the MWM immediatelyfollowing treatment but impairs performance when memoryis tested 28 days later (Hu et al., 2008).

The current experiment investigated the relative con-tributions of angiogenesis and neurogenesis to exercise-induced facilitation of visual spatial memory. Becausethere is evidence to suggest that neurogenesis becomesimportant in visual spatial memory enhancement only afterthe new neurons are functionally incorporated into the

1 Present address: University of Texas, Austin, TX, USA.*Corresponding author. Tel: !1-414-229-5883; fax: !1-414-229-5219.E-mail address: [email protected] (R. A. Swain).Abbreviations: ABC, avidin-biotin complex; AZT-VX, AZT-injected vol-untary exercise; DAB, 3=3-diaminobenzidine; DG, dentate gyrus;DMSO, dimethyl sulfoxide; LSD, least significant difference; MWM,Morris water maze; NGS, normal goat serum; NHS, normal horseserum; PBS, phosphate buffered saline; VEH-IC, DMSO-injected in-active control; VEH-VX, DMSO-injected voluntary exercise; VX, vol-untary exercise.

Neuroscience 171 (2010) 214–226

0306-4522/10 $ - see front matter © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.doi:10.1016/j.neuroscience.2010.08.008

214

proved their performance by 53.17% (!SEM"9.25). Aunivariate ANOVA of the percent change from day one today six confirmed this observation (F(3,33)"2.833, P"0.050), depicted in Fig 5C. Post hoc analyses with an LSDtest revealed that AZT-VX animals performed significantlybetter than VEH-VX (P"0.031) and VEH-IC (P"0.014)animals.

Trials to criterion. Acquisition in the MWM was alsoevaluated using trials to criterion analysis. For our pur-poses, criterion performance was defined as two or moreconsecutive trials with less than a 10 s difference in laten-cies to find the hidden platform. SU5416-VX (M"11.300!SEM"0.386) animals required a larger number oftrialstoreachcriterionperformancethanAZT-VX(M"8.500!SEM"1.195), VEH-VX (M"8.700!SEM"0.970), andVEH-IC (M"6.770!SEM"0.948) animals. This findingwas verified via a univariate ANOVA with trials to criterionas the dependent variable (F(3,33)"5.089, P"0.005), asseen in Fig 5D. Post hoc analyses with an LSD test con-

firmed that SU5416-VX animals required significantly moretrials to reach criterion than AZT-VX (P"0.027), VEH-VX(P"0.030), and VEH-IC (P"0.001) animals.

Velocity data. All animals exhibited equivalent swim-ming abilities, evidenced by similar swim speeds (velocity;mm/s) in the pool. A repeated measures ANOVA with Dayas the repeating factor and velocity as the dependentvariable found a main effect of Day (F(5,.165)"38.940,P#0.001), but no main effect of Treatment (F(3,33)"1.410P"0.257) and no Day * Treatment interaction (F(15,165)"1.505, P"0.108). Average swim speeds by day can beseen in Fig 5E. These findings indicate that the differencesfound in latency (reported above) were the result of differ-ences in learning rates between groups as opposed to anartifact of physical ability.

Probe trial performance. During the first probe trial,which was conducted 24 h after the final day of training, allanimals spent a similar amount of time in the target quad-

Fig. 4. BrdU quantification and NeuN colabel. Tissue was treated with immunohistochemical antibodies targeting BrdU to label dividing cells (indicatedby white arrows) (A). The number of BrdU cells for each group was quantified (B). Tissue was treated with immunofluorescent antibodies targeting(C) NeuN and (D) BrdU. Stained tissue was then imaged at 200$ and images were merged in order to identify co-expression of BrdU and NeuN (E).White arrows indicate examples of BrdU% cells. The percentage of BrdU% cells also expressing NeuN was quantified (F). For interpretation of thereferences to color in this figure legend, the reader is referred to the Web version of this article.

A. L. Kerr et al. / Neuroscience 171 (2010) 214–226 219


ANGIOGENESIS BUT NOT NEUROGENESIS IS CRITICAL FORNORMAL LEARNING AND MEMORY ACQUISITION

A. L. KERR,1 E. L. STEUER, V. POCHTAREV ANDR. A. SWAIN*

University of Wisconsin-Milwaukee, Milwaukee, WI, USA

Abstract—Aerobic exercise has been well established to pro-mote enhanced learning and memory in both human andnon-human animals. Exercise regimens enhance blood per-fusion, neo-vascularization, and neurogenesis in nervoussystem structures associated with learning and memory. Theimpact of specific plastic changes to learning and memoryperformance in exercising animals are not well understood.The current experiment was designed to investigate the con-tributions of angiogenesis and neurogenesis to learning andmemory performance by pharmacologically blocking eachprocess in separate groups of exercising animals prior tovisual spatial memory assessment. Results from our experi-ment indicate that angiogenesis is an important componentof learning as animals receiving an angiogenesis inhibitorexhibit retarded Morris water maze (MWM) acquisition. Inter-estingly, our results also revealed that neurogenesis inhibi-tion improves learning and memory performance in theMWM. Animals that received the neurogenesis inhibitor dis-played the best overall MWM performance. These resultspoint to the importance of vascular plasticity in learning andmemory function and provide empirical evidence to supportthe use of manipulations that enhance vascular plasticity toimprove cognitive function and protect against natural cog-nitive decline. © 2010 IBRO. Published by Elsevier Ltd. Allrights reserved.

Key words: vascular plasticity, exercise-induced facilitation,Morris water maze.

Aerobic exercise promotes enhanced learning and mem-ory in both human and non-human animals. At the cellularlevel, exercise is associated with increased angiogenesis(the sprouting of new capillaries from preexisting bloodvessels) and/or neurogenesis in various areas of the brainincluding the hippocampus, motor cortex and cerebellum(Black et al., 1991; Clark et al., 2009; Isaacs et al., 1992;Kim et al., 2002; Sikorski et al., 2008; Swain et al., 2003;van Praag et al., 2005). Aerobic exercise in rodents is alsoassociated with improved recovery following ischemic in-sult (Lee et al., 2003a,b; Sim et al., 2004) and improved

cognitive performance on a variety of tasks including theMorris water maze (MWM), contextual fear conditioning,extinction of contextual fear, and radial arm maze (Ander-son et al., 2000; Baruch et al., 2004; Fordyce and Wehner,1993; Gobbo and O’Mara, 2004; Pietropaolo et al., 2006;Powell, 2005; Vaynman et al., 2004). In humans, exercisehas been associated with improved cognitive performance inyoung adult, aging adult, and brain-injured populations(Churchill et al., 2002; Grealy et al., 1999; Kramer and Erick-son, 2007; Kramer et al., 2006; Winter et al., 2007) and hasbeen shown to protect against the onset of various demen-tias, including Alzheimer’s disease (Laurin et al., 2001).

The means by which experience facilitates learningand memory are not fully understood. However, the sur-vival of new neurons may contribute to learning and mem-ory changes following exercise. It has been consistentlyshown that both enriched environments and exercise (vol-untary and forced) promote neurogenesis in the adult hip-pocampus, specifically in the dentate gyrus (DG) (Christieet al., 2008; Kempermannn et al., 1997, 1998; Kim et al.,2002; Olson et al., 2006; Uysal et al., 2005; Van der Borghtet al., 2006; van Praag et al., 2005), and exercise-inducedneurogenesis is correlated with improved learning and mem-ory performance (Uysal et al., 2005; van Praag et al., 2005).However, there are also reports that manipulation of neuro-genesis does not impact learning and memory function in theMWM (Meshi et al., 2006; Shors et al., 2002) or contextualfear conditioning (Clark et al., 2008; Shors et al., 2002),indicating that neurogenesis may not be the sole supporter ofenhanced cognitive performance following exercise.

The contribution of neurogenesis to learning and mem-ory function is further complicated by recent evidence sug-gesting that newly proliferated neurons are not immedi-ately and functionally incorporated into existing learningnetworks. While it is clear that new neurons do becomefunctionally integrated into the existing circuitry eventually,several recent reports indicate that this integration is asomewhat delayed process taking between 3 and 4 weeksto complete (Kee et al., 2007; Overstreet et al., 2004; vanPraag et al., 2002). These data are supported by behav-ioral studies indicating that impaired neurogenesis doesnot affect visual spatial memory in the MWM immediatelyfollowing treatment but impairs performance when memoryis tested 28 days later (Hu et al., 2008).

The current experiment investigated the relative con-tributions of angiogenesis and neurogenesis to exercise-induced facilitation of visual spatial memory. Becausethere is evidence to suggest that neurogenesis becomesimportant in visual spatial memory enhancement only afterthe new neurons are functionally incorporated into the

1 Present address: University of Texas, Austin, TX, USA.*Corresponding author. Tel: !1-414-229-5883; fax: !1-414-229-5219.E-mail address: [email protected] (R. A. Swain).Abbreviations: ABC, avidin-biotin complex; AZT-VX, AZT-injected vol-untary exercise; DAB, 3=3-diaminobenzidine; DG, dentate gyrus;DMSO, dimethyl sulfoxide; LSD, least significant difference; MWM,Morris water maze; NGS, normal goat serum; NHS, normal horseserum; PBS, phosphate buffered saline; VEH-IC, DMSO-injected in-active control; VEH-VX, DMSO-injected voluntary exercise; VX, vol-untary exercise.

Neuroscience 171 (2010) 214–226

0306-4522/10 $ - see front matter © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.doi:10.1016/j.neuroscience.2010.08.008

214

SEM!2.498) and VEH-IC (M!26.300%"SEM!1.980)animals, as seen in Fig 6C. These findings were supportedby a univariate ANOVA with the percent of time spent inthe NE quadrant as the dependent variable (F(1,17)!2.877,P!0.050). Post hoc analyses with an LSD test confirmedsignificant differences between AZT-VX and VEH-IC(P!0.040), AZT-VX and SU5416-VX (P!0.035), VEH-VXand VEH-IC (P!0.060), and VEH-VX and SU5416-VX(P!0.050) animals.

As with the first probe trial, the percent of time spent inthe quadrant opposite the target quadrant (SW quadrant)was explored in the remote probe trial in an effort to better

understand performance. As explained above, this vari-able allowed us to assess whether or not animals weresearching in the relative proximity of the platform (in the NEand adjacent quadrants), or if the animals were exploringin a less adaptive fashion by swimming on the oppositeend of the pool (SW quadrant). Results from this analysiscan be seen in Fig 6D. VEH-IC (M!22.533%"SEM!1.966) and SU5416-VX (M!23.890%"SEM!2.619) animals were found to spend significantly more timein the SW quadrant than VEH-VX (M!15.27%"SEM!1.586) and AZT-VX (M!15.113%"SEM!2.140)animals (F(3,33)!5.355, P!0.004). Post hoc analyses with

Fig. 6. MWM one probe trials. (A) All animals spent equivalent amounts of time in the correct quadrant during the first probe trial. (B) All animals alsospent similar amounts of time in the SW quadrant, which is directly opposite the target quadrant and represents the greatest distance from the platformthat animals can search. (C) During the remote probe trial, SU5416-VX and VEH-IC animals spent significantly less time in the correct quadrant thandid AZT-VX and VEH-VX animals. (D) Similarly, SU5416-VX and VEH-IC animals spent significantly more time in the SW quadrant (opposite the targetquadrant) than did AZT-VX and VEH-VX aniamls (* indicates P#0.06).

A. L. Kerr et al. / Neuroscience 171 (2010) 214–226 221


Sistema visualSistema Visual


Age

Cam

bio

s m

edia

dos

por

exp

erie

ncia

Periodo crítico

4ª semana

1º-3ª semanas 4ª-6ª semanas 7ª y 8ª semanas

Periodo precritico Periodo crítico Periodo postcrítico


Empobrecimiento ambiental

Descenso densidades neuronal, glial y vascular

Retraso maduración

Anulación cierre periodo crítico


Empobrecimiento ambiental


Cortical parameters


Vascular density


Results

0

20

40

60

80

100

120

0 DPN 7 DPN 14 DPN 21 DPN 60 DPN

0

5

10

15

20

25

0 DPN 7 DPN 14 DPN 21 DPN 60 DPN

OscuridadControles

Vascular Density Number of perpendicular vessels


Enriquecimiento ambiental

Donald Hebb (1949)

Kresh, Bennett, Rosenzweig, Diamond (60s)

Combinación de complejidad de objetos

inanimados y estimulación social.



Cambios anatómicos

Plasticidad neuronal

Sinaptogénesis

Morfología sináptica

Neurogénesis

Neurotrofinas (BDNF, NGF, NT-3, VEGF)

Gliogénesismartes 15 de noviembre de 2011


Reduce el deficit de memoria tras ictus (Dahlqvist, 2004)

Mejora la recuperiación funcional tras lesión estriatal (Dobrossy 2004)

Induce neurogenesis en hipocampo (Kempermann 1997)

Reduce los efectos del Hungtington (Spires 2004)

Madura y consolida la corteza visual en ratas privadas de luz (Bertoletti 2004)

Revierte los efectos del stress prenatal (Morley-Fletcher 2003)

Acelera el desarrollo de la corteza visual (Cancedda 2004)


Edades :

. 14 dpn, 21 dpn

. 28 dpn, 35 dpn, 42 dpn

. 49 dpn, 56 dpn, 63 dpn

Pre-critical

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0

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4,5

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14 dpn 21 dpn 28 dpn 35 dpn 42 dpn 49 dpn 56 dpn 63 dpn

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Patología SNC

TCE

Ictus

Tumores

Patologías neurodegenerativas


Patología SNC

TCE

Ictus

Tumores


Vascularización


Neuroprotección mediante

enriquecimiento ambiental


Parkinson

Alzheimer

Hungtinton

Ictus

TCEmartes 15 de noviembre de 2011

Objetivos terapeúticos

Neuroprotección/neurorescate

Incremento vascularización


TCE en Desarrollo

Mayor capacidad de plasticidad

Interferencia en los mecanismos fisiológicos

Apoptosis

Plasticidad sináptica (NMDA)


vascularización cerebral (parte ii)

Health & Medicine