Hyperhomocysteinemia and its effect on ageing and language functions - HEAL study.

Hyperhomocysteinemia or high levels (> 15 µmol/L) of homocysteine (Hcy)in the blood has been suggested to affect the brain through vascular and neurodegenerative pathways and potentially impact cognition. The current study aims to explore the association of high homocysteine with cognition and brain volume changes in a cohort of middle and old agedr adults. The study recruited 1296 participants aged ≥ 45 years from Tata Longitudinal Study of Ageing (TLSA), an ongoing cohort study. The participants underwent detailed cognitive assessments using Addenbrooke's Cognitive Examination-III (ACE-III) and Computerized Assessment of Adult Information Processing (COGNITO) neuropsychological battery and MR imaging using a 3T scanner. The participants were classified based on the median homocysteine level (16.89 µmol/L) into low Hcy (≤ median) and high Hcy (> median) groups. When adjusted for age, gender, years of education, vitamin B12, folate and dyslipidaemia, Generalised Linear Model (GLM) found a significant association of high Hcy with vocabulary task [ß (95% CI) - 1.354 (- 2.655, - 0.052); p = 0.041]. Significant associations was also obtained between cerebral white matter volume and high Hcy [ß (95% CI) - 5617.182 (- 11062.762, - 173.602); p = 0.043]. The results suggest that people with high Hcy levels performed poorer in cognitive tasks related to language domain and had lesser cerebral white matter volume. This indicates that homocysteine might have a profound impact on brain structure as well as function.

Recurrent endothelin-1 mediated vascular insult leads to cognitive impairment protected by trophic factor pleiotrophin.

Vascular dementia (VaD) is a complex neurodegenerative condition, with cerebral small vessel dysfunctions as the central role in its pathogenesis. Given the lack of suitable animal models to study the disease pathogenesis, we developed a mouse model to closely emulate the clinical scenarios of recurrent transient ischemic attacks (TIAs) leading to VaD using vasoconstricting peptide Endothelin-1(ET-1). We observed that administration of ET-1 led to blood-brain barrier (BBB) disruption and detrimental changes in its components, such as endothelial cells and pericytes, along with neuronal loss and synaptic dysfunction, resulting in irreversible memory loss. Further, in our pursuit of understanding potential interventions, we co-administered pleiotrophin (PTN) alongside ET-1 injections. PTN exhibited remarkable efficacy in preserving vital components of the BBB, including endothelial cells and pericytes, thereby restoring BBB integrity, preventing neuronal loss, and enhancing memory function. Our findings give a valuable framework for understanding the detrimental effects of multiple TIAs on brain health and provide a useful animal model to explore VaD's underlying mechanisms further and pave the way for promising therapies.

Distribution of biochemical and haematological parameters in an aging population from southern India: A cross-sectional analysis.

BACKGROUND: Examining the distribution of biochemical and haematological tests in different age groups of rural population is necessary to ensure that health care facilities are equipped to address the prevalent health conditions and manage age-related illness effectively. Hence, this study is aimed at seeing the distributions of blood biochemical and haematological parameters in rural population. METHODS: This cross-sectional study investigated the distribution of 26 different haematological and biochemical parameters in longitudinal cohort study (Srinivaspura Aging, NeuoSenescence and COGnition - SANSCOG), from the villages of Srinivaspura, Kolar district, India. A total of 2592 participants (1240 males and 1352 females), aged ≥45 years who are cognitively healthy were included for the analysis. Mean, 2.5th, 5th, 25th, 50th, 75th, 95th and 97.5th percentiles were calculated for the entire sample. Additionally, median and percentiles were determined for both gender and age categories (45-54, 55-64, 65-74, and ≥75 years). RESULTS: We observed the distinct distributions of various haematological and biochemical parameters, with elevated levels of glycaemic, lipid, liver, and thyroid parameters. CONCLUSION: Findings revealed the notable variations from the established reference ranges, indicating the potential undiagnosed cases and highlighting the gaps in health awareness and health seeking behaviour.

Prevalence and patterns of vitamin D deficiency and its role in cognitive functioning in a cohort from South India.

Vitamin D (VitD) is a naturally occurring, fat-soluble vitamin which regulates calcium and phosphate homeostasis in the human body and is also known to have a neuroprotective role. VitD deficiency has often been associated with impaired cognition and a higher risk of dementia. In this study, we aimed to explore the relationship between levels of VitD and cognitive functioning in adult individuals. 982 cognitively healthy adults (≥ 45 years) were recruited as part of the CBR-Tata Longitudinal Study for Aging (TLSA). Addenbrooke's cognitive examination-III (ACE-III) and Hindi mental status examination (HMSE) were used to measure cognitive functioning. 25-hydroxyvitamin D [25(OH)D] levels were measured from the collected serum sample and classified into three groups- deficient (< 20 ng/ml), insufficient (20-29 ng/ml) and normal (≥ 30 ng/ml). Statistical analysis was done using IBM SPSS software, version 28.0.1.1(15). The mean age of the participants was 61.24 ± 9 years. Among 982 participants, 572 (58%) were deficient, 224 (23%) insufficient and only 186 (19%) had normal levels of VitD. Kruskal-Wallis H test revealed a significant difference in age (p = 0.015) and education (p = 0.021) across VitD levels and the Chi-square test revealed a significant association between gender (p = 0.001) and dyslipidemia status (p = 0.045) with VitD levels. After adjusting for age, education, gender and dyslipidemia status, GLM revealed that individuals with deficient (p = 0.038) levels of VitD had lower scores in ACE-III verbal fluency as compared to normal. Additionally, we also found that 91.2% individuals who had VitD deficiency were also having dyslipidemia. It is concerning that VitD deficiency impacts lipid metabolism. Lower levels of VitD also negatively impacts verbal fluency in adult individuals. Verbal fluency involves higher order cognitive functions and this result provides us with a scope to further investigate the different domains of cognition in relation to VitD deficiency and other associated disorders.

Akt activation ameliorates deficits in hippocampal-dependent memory and activity-dependent synaptic protein synthesis in an Alzheimer's disease mouse model.

Protein kinase-B (Akt) and the mechanistic target of rapamycin (mTOR) signaling pathways are implicated in Alzheimer's disease (AD) pathology. Akt/mTOR signaling pathways, activated by external inputs, enable new protein synthesis at the synapse and synaptic plasticity. The molecular mechanisms impeding new protein synthesis at the synapse in AD pathogenesis remain elusive. Here, we aimed to understand the molecular mechanisms prior to the manifestation of histopathological hallmarks by characterizing Akt1/mTOR signaling cascades and new protein synthesis in the hippocampus of WT and amyloid precursor protein/presenilin-1 (APP/PS1) male mice. Intriguingly, compared to those in WT mice, we found significant decreases in pAkt1, pGSK3ß, pmTOR, pS6 ribosomal protein, and p4E-BP1 levels in both post nuclear supernatant and synaptosomes isolated from the hippocampus of one-month-old (presymptomatic) APP/PS1 mice. In synaptoneurosomes prepared from the hippocampus of presymptomatic APP/PS1 mice, activity-dependent protein synthesis at the synapse was impaired and this deficit was sustained in young adults. In hippocampal neurons from C57BL/6 mice, downregulation of Akt1 precluded synaptic activity-dependent protein synthesis at the dendrites but not in the soma. In three-month-old APP/PS1 mice, Akt activator (SC79) administration restored deficits in memory recall and activity-dependent synaptic protein synthesis. C57BL/6 mice administered with an Akt inhibitor (MK2206) resulted in memory recall deficits compared to those treated with vehicle. We conclude that dysregulation of Akt1/mTOR and its downstream signaling molecules in the hippocampus contribute to memory recall deficits and loss of activity-dependent synaptic protein synthesis. In AD mice, however, Akt activation ameliorates deficits in memory recall and activity-dependent synaptic protein synthesis.

Relationship between Framingham Cardiovascular Risk Score and cognitive performance among ageing rural Indian participants: a cross-sectional analysis.

OBJECTIVE: The burden of cardiovascular risk factors is increasing in India, which, in turn, can adversely impact cognition. Our objective was to examine the effect of cardiovascular risk factors measured by Framingham Risk Score (FRS) on cognitive performance among a cohort of healthy, ageing individuals (n=3609) aged ≥45 years from rural India. DESIGN: A cross-sectional analysis. SETTING: A rural community setting in southern India. PARTICIPANTS: Healthy, ageing, dementia-free participants, aged 45 years and above, belonging to the villages of Srinivaspura (a rural community located around 100 km from Bangalore, India), were recruited. PRIMARY OUTCOME MEASURES: Using a locally adapted, validated, computerised cognitive test battery, we assessed cognitive performance across multiple cognitive domains: attention, memory, language, executive functioning and visuospatial ability. RESULTS: The median (IQR) age of the sample was 57 (50.65) and 50.5% were women. Multiple linear regression analysis showed that participants with higher FRS performed poorly in attention (visual attention (ß=-0.018, p=0.041)), executive functioning (categorical fluency (ß=-0.064, p<0.001)), visuospatial ability (form matching (ß=-0.064, p<0.001) and visuospatial span (ß=-0.020, p<0.001)), language (reading and sentence comprehension (ß=-0.010, p=0.013), word comprehension (ß=-0.021, p<0.001) and semantic association (ß=-0.025, p<0.001)), and memory (episodic memory IR (ß=-0.056, p<0.001), episodic memory DR (ß=-0.076, p<0.001) and name-face association (ß=-0.047, p<0.001)). CONCLUSION: Increased cardiovascular risk as evidenced by FRS was associated with poorer cognitive performance in all cognitive domains among dementia-free middle-aged and older rural Indians. It is imperative to design and implement appropriate interventions (pharmacological and lifestyle-based) for cardiovascular risk reduction and thereby, prevent or mitigate accelerated cognitive impairment in ageing individuals.

Sex difference in evolution of cognitive decline: studies on mouse model and the Dominantly Inherited Alzheimer Network cohort.

Women carry a higher burden of Alzheimer's disease (AD) compared to men, which is not accounted entirely by differences in lifespan. To identify the mechanisms underlying this effect, we investigated sex-specific differences in the progression of familial AD in humans and in APPswe/PS1ΔE9 mice. Activity dependent protein translation and associative learning and memory deficits were examined in APPswe/PS1ΔE9 mice and wild-type mice. As a human comparator group, progression of cognitive dysfunction was assessed in mutation carriers and non-carriers from DIAN (Dominantly Inherited Alzheimer Network) cohort. Female APPswe/PS1ΔE9 mice did not show recall deficits after contextual fear conditioning until 8 months of age. Further, activity dependent protein translation and Akt1-mTOR signaling at the synapse were impaired in male but not in female mice until 8 months of age. Ovariectomized APPswe/PS1ΔE9 mice displayed recall deficits at 4 months of age and these were sustained until 8 months of age. Moreover, activity dependent protein translation was also impaired in 4 months old ovariectomized APPswe/PS1ΔE9 mice compared with sham female APPswe/PS1ΔE9 mice. Progression of memory impairment differed between men and women in the DIAN cohort as analyzed using linear mixed effects model, wherein men showed steeper cognitive decline irrespective of the age of entry in the study, while women showed significantly greater performance and slower decline in immediate recall (LOGIMEM) and delayed recall (MEMUNITS) than men. However, when the performance of men and women in several cognitive tasks (such as Wechsler's logical memory) are compared with the estimated year from expected symptom onset (EYO) we found no significant differences between men and women. We conclude that in familial AD patients and mouse models, females are protected, and the onset of disease is delayed as long as estrogen levels are intact.

Protein Glutathionylation and Glutaredoxin: Role in Neurodegenerative Diseases.

Oxidative stress has been implicated in the pathogenesis and progression of many neurodegenerative disorders including Parkinson's disease and Alzheimer's disease. One of the major enzyme systems involved in the defense against reactive oxygen species are the tripeptide glutathione and oxidoreductase glutaredoxin. Glutathione and glutaredoxin system are very important in the brain because of the oxidative modification of protein thiols to protein glutathione mixed disulfides with the concomitant formation of oxidized glutathione during oxidative stress. Formation of Pr-SSG acts as a sink in the brain and is reduced back to protein thiols during recovery, thus restoring protein functions. This is unlike in the liver, which has a high turnover of glutathione, and formation of Pr-SSG is very minimal as liver is able to quickly quench the prooxidant species. Given the important role glutathione and glutaredoxin play in the brain, both in normal and pathologic states, it is necessary to study ways to augment the system to help maintain the protein thiol status. This review details the importance of glutathione and glutaredoxin systems in several neurodegenerative disorders and emphasizes the potential augmentation of this system as a target to effectively protect the brain during aging.

Endothelin-1 mediated vasoconstriction leads to memory impairment and synaptic dysfunction.

Cerebrovascular lesions seen as white matter hyperintensity in MRI of elderly population caused due to micro-infracts and micro-bleeds contributes to vascular dementia. Such vascular insult caused by impairment in blood flow to specific area in brain involving small vessels can gradually worsen the pathology leading to cognitive deficits. In the present study we developed a transient model of vaso-constriction to study the impact of such pathology by bilateral injection of ET-1 (Endothelin-1; a 21 amino acid vasoconstricting peptide) into lateral ventricles of C57 mice. The impediment in cerebral blood flow decreased CD31 expression in endothelial cells lining the blood vessels around the hippocampal region, leading to memory deficits after 7 days. Activity dependent protein translation, critical for synaptic plasticity was absent in synaptoneurosomes prepared from hippocampal tissue. Further, Akt1- mTOR signaling cascade was downregulated indicating the possible cause for loss of activity dependent protein translation. However, these effects were reversed after 30 days indicating the ephemeral nature of deficits following a single vascular insult. Present study demonstrates that vasoconstriction leading to memory deficit and decline in activity dependent protein translation in hippocampus as a potential molecular mechanism impacting synaptic plasticity.

Glutaredoxin 1 Downregulation in the Substantia Nigra Leads to Dopaminergic Degeneration in Mice.

BACKGROUND: Parkinson's disease (PD) is characterized by a severe loss of the dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Perturbation of protein thiol redox homeostasis has been shown to play a role in the dysregulation of cell death and cell survival signaling pathways in these neurons. Glutaredoxin 1 (Grx1) is a thiol/disulfide oxidoreductase that catalyzes the deglutathionylation of proteins and is important for regulation of cellular protein thiol redox homeostasis. OBJECTIVES: We evaluated if the downregulation of Grx1 could lead to dopaminergic degeneration and PD-relevant motor deficits in mice. METHODS: Grx1 was downregulated unilaterally through viral vector-mediated transduction of short hairpin RNA against Grx1 into the SNpc. Behavioral assessment was performed through rotarod and elevated body swing test. Stereological analysis of tyrosine hydroxylase-positive and Nissl-positive neurons was carried out to evaluate neurodegeneration. RESULTS: Downregulation of Grx1 resulted in contralateral bias of elevated body swing and reduced latency to fall off, accelerating rotarod. This was accompanied by a loss of tyrosine hydroxylase-positive neurons in the SNpc and their DA projections in the striatum. Furthermore, there was a loss Nissl-positive neurons in the SNpc, indicating cell death. This was selective to the SNpc neurons because DA neurons in the ventral tegmental area were unaffected akin to that seen in human PD. Furthermore, Grx1 mRNA expression was substantially decreased in the SNpc from PD patients. CONCLUSIONS: Our study indicates that Grx1 is critical for the survival of SNpc DA neurons and that it is downregulated in human PD. © 2020 International Parkinson and Movement Disorder Society.

Isoform-specific hyperactivation of calpain-2 occurs presymptomatically at the synapse in Alzheimer's disease mice and correlates with memory deficits in human subjects.

Calpain hyperactivation is implicated in late-stages of neurodegenerative diseases including Alzheimer's disease (AD). However, calpains are also critical for synaptic function and plasticity, and hence memory formation and learning. Since synaptic deficits appear early in AD pathogenesis prior to appearance of overt disease symptoms, we examined if localized dysregulation of calpain-1 and/or 2 contributes to early synaptic dysfunction in AD. Increased activity of synaptosomal calpain-2, but not calpain-1 was observed in presymptomatic 1 month old APPswe/PS1ΔE9 mice (a mouse model of AD) which have no evident pathological or behavioural hallmarks of AD and persisted up to 10 months of age. However, total cellular levels of calpain-2 remained unaffected. Moreover, synaptosomal calpain-2 was hyperactivated in frontal neocortical tissue samples of post-mortem brains of AD-dementia subjects and correlated significantly with decline in tests for cognitive and memory functions, and increase in levels of ß-amyloid deposits in brain. We conclude that isoform-specific hyperactivation of calpain-2, but not calpain-1 occurs at the synapse early in the pathogenesis of AD potentially contributing to the deregulation of synaptic signaling in AD. Our findings would be important in paving the way for potential therapeutic strategies for amelioration of cognitive deficits observed in ageing-related dementia disorders like AD.

Synthesis and biological evaluation of boswellic acid-NSAID hybrid molecules as anti-inflammatory and anti-arthritic agents.

Methyl esters of the ß-boswellic acid (BA) and 11-keto-ß-boswellic acid (KBA) obtained from Boswellia serrata resin were subjected to Steglich esterification with the different non-steroidal anti-inflammatory drugs (NSAID) viz., ibuprofen, naproxen, diclophenac and indomethacin. The novel hybrids of methyl boswellate (5-8) and that of methyl 11-keto boswellate (9-12) were evaluated for anti-inflammatory activity by carrageenan-induced rat hind paw edema model and anti-arthritic activity by Complete Freund's Adjuvant (CFA) induced arthritis in Wister albino rat. Significant inhibition on carrageenan-induced paw edema has been observed with 5, 6 and 10 where as in CFA induced rats, hybrids 5, 8, 9 and 12 exhibited pronounced antiarthritic activity. Hybrid molecules 5 and 9 have been found to be more effective in inhibiting in-vivo COX-2 than ibuprofen by itself, thus showing the synergistic effect. Hybrid 5 and 9 tested for in-vitro lipoxygenase and cyclooxygenase-2 (LOX/COX-2) inhibitory activity. The studies revealed that both 5 and 9 inhibited COX-2 relatively better than LOX enzyme.

Nitro Derivatives of Naturally Occurring ß -Asarone and Their Anticancer Activity.

ß-Asarone (2, 4, 5-trimethoxy-(Z)-1-propenylbenzene) was obtained from Acorus calamus. Nitration of ß-asarone with AgNO2/I2 in ether yielded 1-(2, 4, 5-trimethoxy phenyl)-2-nitropropene (1) but with NaNO2/I2 in ethylene glycol obtained 1-(2, 4, 5-trimethoxy phenyl)-1-nitropropene (2). Compound 2 was prepared for the first time and characterized using IR, (1)H-NMR, (13)C-NMR, and GC-MS spectra and it was converted into 1-(2, 4, 5-trimethoxy) phenyl-1-propanone (3) using modified Nef reaction. Based on 1D NOESY experiments, compounds 1 and 2 have been assigned E configuration. Compounds 1 and 2 were subjected to cytotoxic activity using five human cancer cell lines, namely, MCF-7, SW-982, HeLa, PC-3, and IMR-32 by MTT assay. Except in breast cancer line (MCF-7) compound 2 exhibited five- to tenfold increase in activity compared to ß-asarone and twofold increase over compound 1.

Synthetic racemates of abyssinone I and II induces apoptosis through mitochondrial pathway in human cervix carcinoma cells.

Abyssinones I and II are prenylated flavanones existing in plant Erythrina abyssinica showing diverse biological activities including anticancer activities. We synthesized racemic mixtures of these flavanones from corresponding chalcones and herein we report for the first time the molecular mechanisms of cell death, anti-proliferative effect and ability to induce apoptosis in human cervical carcinoma (HeLa) cells. Cytotoxicity was assessed by MTT assay to determine LD50 for prenylated chalcones and their corresponding flavones. Abyssinones promoted apoptosis by up regulation of p53 and Bax, along with down regulation of Bcl-2. Apoptosis induction was mediated through mitochondrial pathway releasing cytochrome c and Apaf-1 into cytosol; associated with activation of caspase-3. Further they were able to decrease the expression of cell proliferation markers PCNA and cyclin D1 indicating anti proliferative activity. These observations demonstrate that abyssinones trigger apoptosis via mitochondrial pathway by activation of caspase-3 and disrupts cell cycle.

Chemomechanical Caries Removal: A Review & Study of an Indigen-ously Developed Agent (Carie Care (TM) Gel) In Children.

The invention and application of engine driven or rotary instruments in operative treatment of carious lesions has resulted in removal of considerable toothe structure. However, with the introduction of adhesive materials for restorations, and the advent of minimal cavity design this principle has been challenged and is now considered to be too destructive to the tooth structure during caries removal. A number of techniques are available for cutting tooth tissue. The chemo mechanical method of caries removal/treatment is considered to be less painful when compared to the traditional treatment method (use of drill). The present study was carried to study the effect of an indigenously developed caries removal agent viz. Carie Care (TM) & its effectiveness as a chemo mechanical caries removal agent. How to cite this article: Venkataraghavan K, Kush A, Lakshminarayana CS, Diwakar L, Ravikumar P, Patil S, Karthik S. Chemomechanical Caries Removal: A Review & Study of an Indigenously Developed Agent (Carie Care (TM) Gel) In Children. J Int Oral Health 2013; 5(4):84-90.

Synthesis, anticancer and antioxidant activities of 2,4,5-trimethoxy chalcones and analogues from asaronaldehyde: structure-activity relationship.

2,4,5-Trimethoxy chalcones and analogues were synthesized from asaronaldehyde derived from ß-asarone. These novel compounds when tested against three human tumour cell lines (MCF-7, SW-982 and HeLa) using MTT assay, revealed that chalcones possessing electron donor groups in para position to carbonyl moiety of phenyl ring A, showed better inhibitory activity (2, 3, 4, 6, 7, 10, 17). When evaluated for antioxidant activities, compound 15 exhibited better free radical scavenging property in DPPH assay while compounds 2, 3, 5, 7, 9, 10, 11, 16, and 18 showed significant NO scavenging activity. All compounds exhibited very good phenyl hydrazine induced haemolysis of erythrocytes in phenylhydrazine assay. Structure-activity relationship (SAR) study using in-silico analysis matched well with in-vitro tumour cell inhibitory activity.

Abyssinones and related flavonoids as potential steroidogenesis modulators.

Abyssinones and related flavonoids were screened against 3 enzymes (3betaHSD, 17betaHSD and Aromatase) of steroidogenesis pathway. The virtual screening experiment shows high affinity for flavonones than their respective chalcones. A 4' -OH blocked prenylated flavonone 2b (2-(2', 2'-dimethyl chroman-6'-yl)-7-hydroxy chroman-4-one) had consistent binding affinity to all the three enzymes used in this study showing higher binding affinity to aromatase. A good correlation was observed between cytotoxic data (MCF-7, breast cancer cell line) and docking results indicating flavonone as a better steroidogenesis modulator in hormone dependent cancer.

Complex I assay in mitochondrial preparations from CNS.

Mammalian NADH:ubiquinone oxidoreductase (complex I) is made up of at least 46 subunits and is one of the largest enzyme complexes known. It catalyzes the first step of the respiratory electron transport chain through the oxidation of NADH, providing two electrons for the reduction of ubiquinone to ubiquinol, thus propelling protons across the inner membrane of the mitochondria, which subsequently drive ATP synthesis. Dysfunction of complex I has been implicated in various neurodegenerative disorders, and it is probably the most vulnerable component of the electron transport chain to inhibition by reactive oxygen species. We describe a simple spectrophotometric method for estimating the activity of complex I from mitochondria isolated from regions of the central nervous system of mice.

Downregulation of glutaredoxin but not glutathione loss leads to mitochondrial dysfunction in female mice CNS: implications in excitotoxicity.

Oxidative stress, excitotoxicity and mitochondrial dysfunction play synergistic roles in neurodegeneration. Maintenance of thiol homeostasis is important for normal mitochondrial function and dysregulation of protein thiol homeostasis by oxidative stress leads to mitochondrial dysfunction and neurodegeneration. We examined the critical roles played by the antioxidant, non-protein thiol, glutathione and related enzyme, glutaredoxin in maintaining mitochondrial function during excitotoxicity caused by beta-N-oxalyl amino-L-alanine (L-BOAA), the causative factor of neurolathyrism, a motor neuron disease involving the pyramidal system. L-BOAA causes loss of GSH and inhibition of mitochondrial complex I in lumbosacral cord of male mice through oxidation of thiol groups, while female mice are resistant. Reducing GSH levels in female mice CNS by pretreatment with diethyl maleate or L-propargyl glycine did not result in inhibition of complex I activity, unlike male mice. Further, treatment of female mice depleted of GSH with L-BOAA did not induce inhibition of complex I indicating that GSH levels were not critical for maintaining complex I activity in female mice unlike their male counterpart. Glutaredoxin, a thiol disulfide oxidoreductase helps maintain redox status of proteins and downregulation of glutaredoxin results in loss of mitochondrial complex I activity. Female mice express higher levels of glutaredoxin in certain CNS regions and downregulation of glutaredoxin using antisense oligonucleotides sensitizes them to L-BOAA toxicity seen as mitochondrial complex I loss. Ovariectomy downregulates glutaredoxin and renders female mice vulnerable to L-BOAA toxicity as evidenced by activation of AP1, loss of GSH and complex I activity indicating the important role of glutaredoxin in neuroprotection. Estrogen protects against mitochondrial dysfunction caused by excitotoxicity by maintaining cellular redox status through higher constitutive expression of glutaredoxin in the CNS. Therapeutic interventions designed to upregulate glutaredoxin may offer neuroprotection against excitotoxicity in motor neurons.