- Email: [email protected]
ROSIGLITAZONE SYNERGISES THE NEUROPROTECTIVE EFFECTS OF VALPROIC ACID AGAINST QUINOLINIC ACID INDUCED NEUROTOXICITY AND ASSOCIATED COGNITIVE IMPAIRMENT IN RATS: TARGETING PPARγ AND HDAC PATHWAYS
Poster Presentations: P2 Background: The association of late-life depression with both systemic low-grade inflammation and cognitive impairment is well established, however the relation between inflammation and cognition in depressed older persons is still unclear. Neutrophil Gelatinase-Associated Lipocalin (NGAL) has recently been identified as neuroinflammatory component in early stages of Alzheimer’s disease and cerebrovascular disease. The aim of this study was to examine the association between plasma NGAL levels and cognitive functioning in late-life depression and the potentially moderating role of gender. Methods: Depressed older persons (n¼369), aged from 60 to 90 years from The Netherlands study of Depression in Older persons (NESDO) cohort were included. Four cognitive domains, i.e. verbal memory, processing speed, executive functioning and working memory were assessed. Plasma NGAL concentrations were analyzed with ELISA analyses and entered in multiple linear regression analyses predicting the cognitive domains adjusted for confounders. Results: The association between increased NGAL levels and poorer performance of specific cognitive domains were gender-specific. Higher NGAL levels were associated with poorer verbal memory and lower processing speed in women. In men, higher NGAL levels wereassociated with impaired executive functioning. No associations were found with working memory. Conclusions: This study shows gender-specific association of NGAL with cognitive functioning in late-life depression. Increased NGAL may be associated with impairment in specific cognitive domains in high risk groups to develop Alzheimer’s disease in females and vascular dementia in males.
P2-138
ROSIGLITAZONE SYNERGISES THE NEUROPROTECTIVE EFFECTS OF VALPROIC ACID AGAINST QUINOLINIC ACID INDUCED NEUROTOXICITY AND ASSOCIATED COGNITIVE IMPAIRMENT IN RATS: TARGETING PPARg AND HDAC PATHWAYS 1
P521
Table 1 Grouping of the experimental animals Sl. No.
Group
Treatment
1 2 3
Naive Sham Control (QA)
4
Rosi (10) per se
5
VPA (200) per se
6
Rosi (5)
7
Rosi (10)
8
VPA (100)
9
VPA (200)
10
Rosi (5) + VPA (100)
Healthy animals (no treatment) Surgery performed, vehicle administered Single intrastriatal bilateral QA (200 nmol/ 2ml) administration Rosiglitazone (10 mg/kg, i.p.) administered to sham animals Valproic acid (200 mg/kg, i.p.) administered to sham animals Rosiglitazone (5 mg/kg, i.p.) administered to QA (300 nmol/4ml) administered animals Rosiglitazone (10 mg/kg, i.p.) administered to QA (300 nmol/4ml) administered animals Valproic acid (100 mg/kg, i.p.) administered to QA (300 nmol/4ml) administered animals Valproic acid (200 mg/kg, i.p.) administered to QA (300 nmol/4ml) administered animals Rosiglitazone (5 mg/kg, i.p.) + Valproic acid (100 mg/kg, i.p.) administered to QA (300 nmol/4ml) administered animals
2 1
Jitendriya Mishra , Anil - Kumar , University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India; 2Panjab University, Chandigarh, India. Contact e-mail: jitendriyamishra@gmail. com Background: Quinolinic acid (QA) causes excitotoxicity by stimulating Nmethyl-D-aspartate (NMDA) receptors via calcium overload leading to neurodegeneration. Neuroprotective potential of peroxisome proliferator activated receptor-g (PPARg) agonists and histone deacetylase (HDAC) inhibitors have been well documented in experimental models of neurodegenerative disorders; however, their exact mechanisms are not clear. Oxidative damage, neuro-inflammation, apoptosis, protein aggregation and signalling of neurotrophic factors are some of the common cellular pathways involved in QA mediated neurotoxicity.Therefore, present study has been designed to explore possible neuroprotective mechanism of valproic acid and its interaction with rosiglitazone against QA induced HD like symptoms in rats. Methods: QA (200 nmol) was administered intrastriatally and bilaterally to the rats. Animals were treated with rosiglitazone, valproate and their combination for 21 days following QA administration. Several behavioural and biochemical parameters were accessed in weekly interval for 21 days. Results: Single bilateral intrastriatal QA (200 nmol/2 ml saline) administration significantly caused motor incordination, memory impairment, oxidative damage, mitochondrial dysfunction (Complex I, II, II and IV), cellular alterations [tumour necrosis factor-alpha (TNF-a), caspase-3, brain derived neurotrophic factor (BDNF), acetylcholinesterase) and striatal neurodegeneration as compared to sham group. Treatment with rosiglitazone (5, 10 mg/ kg) and valproic acid (100, 200 mg/kg) for 21 days significantly attenuated these behavioral, biochemical and cellular alterations as compared to control (QA 200 nmol) group. However, valproic acid (100 mg/kg) treatment in combination with rosiglitazone (5 mg/kg) for 21 days synergised their neuroprotective effect which was significant as compared to their effects per se in QA treated animals. Conclusions: The present study provides an evidence of possible interplay of PPARg agonists and HDAC inhibitors as a novel therapeutic strategy in the management of motor dysfunction and associated cognitive impairment.
P2-139
NEURONAL DENSITY REDUCTION IN BRAINS OF ELDERLY PEOPLE AFFECTED BY OBSESSIVECOMPULSIVE SYMPTOMS
Katia C. Cristina de Oliveira1, Lea Tenenholz Grinberg2, Beny Lafer3, Fabiano Gonc¸alves Nery4, Marcelo Queiroz Hoexter1, Luzia Carreira Lima4, Ana Tereza Di Lorenzo Alho5, Jose Marcelo Farfel6, Claudia Suemoto7, Alexandre Duarte Gigante4, Renata Eloah de Lucena Ferretti-Rebusttini4, Renata Elaine Paraizo Leite8, Ricardo Caires Neves1, Camila F. Nascimento1, Alexandre V. da Silva8, Helena Brentani4, Ricardo Nitrini9, Eurıpedes Constantino Miguel1, Wilson Jacob-Filho10, Helmut Heinsen11, Carlos A. Pasqualucci6, 1University of Sao Paulo Medical School, Sao Paulo, Sao Paulo, Brazil; 2UCSF, San Francisco, California, United States; 3University of Sao Paulo Medical School, S~ao Paulo, Brazil; 4University of Sao Paulo, Sao Paulo, S~ao Paulo, Brazil; 5 University of Sao Paulo, S~ao Paulo, Brazil; 6University of Sao Paulo Medical School, Sao Paulo, Brazil; 7University of S~ao Paulo Medical School, Sao Paulo, Brazil; 8University of Sao Paulo Medical School, S~ao Paulo, Brazil; 9University of S~ao Paulo, Sao Paulo, Brazil; 10University of S~ao APulo, Sao Paulo, Brazil; 11University of Wuerzburg, W€urzburg, Germany. Contact e-mail: [email protected]
P2-138
ROSIGLITAZONE SYNERGISES THE NEUROPROTECTIVE EFFECTS OF VALPROIC ACID AGAINST QUINOLINIC ACID INDUCED NEUROTOXICITY AND ASSOCIATED COGNITIVE IMPAIRMENT IN RATS: TARGETING PPARg AND HDAC PATHWAYS 1
P521
Table 1 Grouping of the experimental animals Sl. No.
Group
Treatment
1 2 3
Naive Sham Control (QA)
4
Rosi (10) per se
5
VPA (200) per se
6
Rosi (5)
7
Rosi (10)
8
VPA (100)
9
VPA (200)
10
Rosi (5) + VPA (100)
Healthy animals (no treatment) Surgery performed, vehicle administered Single intrastriatal bilateral QA (200 nmol/ 2ml) administration Rosiglitazone (10 mg/kg, i.p.) administered to sham animals Valproic acid (200 mg/kg, i.p.) administered to sham animals Rosiglitazone (5 mg/kg, i.p.) administered to QA (300 nmol/4ml) administered animals Rosiglitazone (10 mg/kg, i.p.) administered to QA (300 nmol/4ml) administered animals Valproic acid (100 mg/kg, i.p.) administered to QA (300 nmol/4ml) administered animals Valproic acid (200 mg/kg, i.p.) administered to QA (300 nmol/4ml) administered animals Rosiglitazone (5 mg/kg, i.p.) + Valproic acid (100 mg/kg, i.p.) administered to QA (300 nmol/4ml) administered animals
2 1
Jitendriya Mishra , Anil - Kumar , University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India; 2Panjab University, Chandigarh, India. Contact e-mail: jitendriyamishra@gmail. com Background: Quinolinic acid (QA) causes excitotoxicity by stimulating Nmethyl-D-aspartate (NMDA) receptors via calcium overload leading to neurodegeneration. Neuroprotective potential of peroxisome proliferator activated receptor-g (PPARg) agonists and histone deacetylase (HDAC) inhibitors have been well documented in experimental models of neurodegenerative disorders; however, their exact mechanisms are not clear. Oxidative damage, neuro-inflammation, apoptosis, protein aggregation and signalling of neurotrophic factors are some of the common cellular pathways involved in QA mediated neurotoxicity.Therefore, present study has been designed to explore possible neuroprotective mechanism of valproic acid and its interaction with rosiglitazone against QA induced HD like symptoms in rats. Methods: QA (200 nmol) was administered intrastriatally and bilaterally to the rats. Animals were treated with rosiglitazone, valproate and their combination for 21 days following QA administration. Several behavioural and biochemical parameters were accessed in weekly interval for 21 days. Results: Single bilateral intrastriatal QA (200 nmol/2 ml saline) administration significantly caused motor incordination, memory impairment, oxidative damage, mitochondrial dysfunction (Complex I, II, II and IV), cellular alterations [tumour necrosis factor-alpha (TNF-a), caspase-3, brain derived neurotrophic factor (BDNF), acetylcholinesterase) and striatal neurodegeneration as compared to sham group. Treatment with rosiglitazone (5, 10 mg/ kg) and valproic acid (100, 200 mg/kg) for 21 days significantly attenuated these behavioral, biochemical and cellular alterations as compared to control (QA 200 nmol) group. However, valproic acid (100 mg/kg) treatment in combination with rosiglitazone (5 mg/kg) for 21 days synergised their neuroprotective effect which was significant as compared to their effects per se in QA treated animals. Conclusions: The present study provides an evidence of possible interplay of PPARg agonists and HDAC inhibitors as a novel therapeutic strategy in the management of motor dysfunction and associated cognitive impairment.
P2-139
NEURONAL DENSITY REDUCTION IN BRAINS OF ELDERLY PEOPLE AFFECTED BY OBSESSIVECOMPULSIVE SYMPTOMS
Katia C. Cristina de Oliveira1, Lea Tenenholz Grinberg2, Beny Lafer3, Fabiano Gonc¸alves Nery4, Marcelo Queiroz Hoexter1, Luzia Carreira Lima4, Ana Tereza Di Lorenzo Alho5, Jose Marcelo Farfel6, Claudia Suemoto7, Alexandre Duarte Gigante4, Renata Eloah de Lucena Ferretti-Rebusttini4, Renata Elaine Paraizo Leite8, Ricardo Caires Neves1, Camila F. Nascimento1, Alexandre V. da Silva8, Helena Brentani4, Ricardo Nitrini9, Eurıpedes Constantino Miguel1, Wilson Jacob-Filho10, Helmut Heinsen11, Carlos A. Pasqualucci6, 1University of Sao Paulo Medical School, Sao Paulo, Sao Paulo, Brazil; 2UCSF, San Francisco, California, United States; 3University of Sao Paulo Medical School, S~ao Paulo, Brazil; 4University of Sao Paulo, Sao Paulo, S~ao Paulo, Brazil; 5 University of Sao Paulo, S~ao Paulo, Brazil; 6University of Sao Paulo Medical School, Sao Paulo, Brazil; 7University of S~ao Paulo Medical School, Sao Paulo, Brazil; 8University of Sao Paulo Medical School, S~ao Paulo, Brazil; 9University of S~ao Paulo, Sao Paulo, Brazil; 10University of S~ao APulo, Sao Paulo, Brazil; 11University of Wuerzburg, W€urzburg, Germany. Contact e-mail: [email protected]