Sirtuins are evolutionarily conserved proteins that use nicotinamide adenine dinucleotide (NAD
) as a co-substrate in their enzymatic reactions. There are seven proteins (SIRT1-7) in the human ...sirtuin family, among which SIRT1 is the most conserved and characterized. SIRT1 in the brain, in particular, within the hypothalamus, plays crucial roles in regulating systemic energy homeostasis and circadian rhythm. Apart from this, SIRT1 has also been found to mediate beneficial effects in neurological diseases. In this review, we will first summarize how SIRT1 in the brain relates to obesity, type 2 diabetes, and circadian synchronization, and then we discuss the neuroprotective roles of brain SIRT1 in the context of cerebral ischemia and neurodegenerative disorders.
Sirtuins are an evolutionarily conserved family of regulatory proteins that function in an NAD
-dependent manner. The mammalian family of sirtuins is composed of seven histone deacetylase and ...ADP-ribosyltransferase proteins (SIRT1-SIRT7) that are found throughout the different cellular compartments of the cell. Sirtuins in the brain have received considerable attention in cognition due to their role in a plethora of metabolic and age-related diseases and their ability to induce neuroprotection. More recently, sirtuins have been shown to play a role in normal physiological cognitive function, and aberrant sirtuin function is seen in pathological cellular states. Sirtuins are believed to play a role in cognition through enhancing synaptic plasticity, influencing epigenetic regulation, and playing key roles in molecular pathways involved with oxidative stress affecting mitochondrial function. This review aims to discuss recent advances in the understanding of the role of mammalian sirtuins in cognitive function and the therapeutic potential of targeting sirtuins to ameliorate cognitive deficits in neurological disorders.
Stroke and cardiac arrest result in cerebral ischemia, a highly prevalent medical issue around the world, which is characterized by a reduction or loss of blood flow to the brain. The loss of ...adequate nutrient supply in the brain during ischemia results in neuronal cell death contributing to cognitive and motor deficits that are usually permanent. Current effective therapies for cerebral ischemia are only applicable after the fact. Thus, the development of preventative therapies of ischemia is imperative. A field of research that continues to show promise in developing therapies for cerebral ischemia is ischemic preconditioning (IPC). IPC is described as exposure to sublethal ischemic events, which induce adaptive changes that provide tolerance to future ischemic events. Through either transient sub-lethal ischemic events, or the actions of a preconditioning molecular mimetic, IPC typically results in augmented gene expression and cellular metabolism. A pivotal target of such changes in gene expression and metabolism is the mitochondrion. Direct and indirect effects on mitochondria by IPC can result in the activation of 5' adenosine monophosphate-activated protein kinase (AMPK), a master regulator of cellular metabolism. Changes in the activity of the posttranslational modifiers, SIRT1 and SIRT5, also contribute to the overall adaptive processes in cellular metabolism and mitochondrial functioning. In this review, we present recently collected evidence to highlight the neuroprotective interactions of mitochondria with AMPK, SIRT1, and SIRT5 in IPC. To produce this review, we utilized PubMed and previous reviews to target and to consolidate the relevant studies and lines of evidence.
Abstract only Sirt1 has been implicated to play a major role in ischemic preconditioning (IPC)—a phenomenon whereby a sublethal episode of ischemia induces tolerance to a subsequent prolonged ...ischemic insult, such as stroke. Both IPC and pharmacological mimetics (i.e. resveratrol) upregulate Sirt1 activity and expression. Since Sirt1 is thought to regulate the expression of proteins involved in synaptic plasticity, neuroprotection afforded by Sirt1 may be explained by changes in these processes. For this reason, we investigated the effects of Sirt1 deficiency on long-term potentiation (LTP). Using inducible, neuronal-specific Sirt1 knockout mice, acute brain slices were prepared and extracellular field recordings were taken in the CA1 region of the hippocampus. Sirt1 deficiency significantly increased LTP induction (2.08 ± 0.065 fold change relative to a 1.46 ± 0.054 change in wild-type mice; n = 10-11, p = 0.022), suggesting Sirt1 may function to repress the transcription of genes associated with LTP. Paired-pulse facilitation was also significantly increased, where neuronal Sirt1 knockout mice had a 2.10 ± 0.047 fold increase in the paired-pulse response after LTP compared to that of the wild-type control (1.60 ± 0.040; n = 10-11, p = 0.001). These changes were indicative of presynaptic involvement. To test whether similar changes in plasticity occur during the late phase of preconditioning, wild-type mice were treated with resveratrol or a vehicle control and subjected to electrophysiological recordings ex vivo 48 hours later. However, no differences in LTP induction or paired-pulse facilitation were observed. Thus, it is unclear whether protection mediated by resveratrol preconditioning involves changes in synaptic plasticity. Since Sirt1 is capable of deacetylating many histone and non-histone proteins, its effects on transcription and gene expression may vary depending on its activity and period of activation. It is probable that during the extended window of ischemic tolerance, Sirt1 may exert different effects than that of the early or classical late phase. Thus, future studies investigating the effects of Sirt1 on plasticity across different time windows of IPC may shed light on new, more direct targets that can mimic or facilitate preconditioning.
Cerebral ischemia remains a leading cause of mortality worldwide. Although the incidence of death has decreased over the years, surviving patients may suffer from long-term cognitive impairments and ...have an increased risk for dementia. Unfortunately, research aimed toward developing therapies that can improve cognitive outcomes following cerebral ischemia has proved difficult given the fact that little is known about the underlying processes involved. Nevertheless, mechanisms that disrupt neural network activity may provide valuable insight, since disturbances in both local and global networks in the brain have been associated with deficits in cognition. In this review, we suggest that abnormal neural dynamics within different brain networks may arise from disruptions in synaptic plasticity processes and circuitry after ischemia. This discussion primarily concerns disruptions in local network activity within the hippocampus and other extra-hippocampal components of the Papez circuit, given their role in memory processing. However, impaired synaptic plasticity processes and disruptions in structural and functional connections within the Papez circuit have important implications for alterations within the global network, as well. Although much work is required to establish this relationship, evidence thus far suggests there is a link. If pursued further, findings may lead toward a better understanding of how deficits in cognition arise, not only in cerebral ischemia, but in other neurological diseases as well.
Stroke remains a leading cause of mortality; however, available therapeutics are limited. The study of ischemic tolerance, in paradigms such as resveratrol preconditioning (RPC), provides promise for ...the development of novel prophylactic therapies. The heavily oxidative environment following stroke promotes poly-ADP-ribose polymerase 1 (PARP1)-overactivation and parthanatos, both of which are major contributors to neuronal injury. In this study, we tested the hypothesis that RPC instills ischemic tolerance through decreasing PARP1 overexpression and parthanatos following in vitro and in vivo cerebral ischemia. To test this hypothesis, we utilized rat primary neuronal cultures (PNCs) and middle cerebral artery occlusion (MCAO) in the rat as in vitro and in vivo models, respectively. RPC was administered 2 days preceding ischemic insults. RPC protected PNCs against oxygen and glucose deprivation (OGD)–induced neuronal loss, as well as increases in total PARP1 protein, implying protection against PARP1-overactivation. Twelve hours following OGD, we observed reductions in NAD
+
/NADH as well as an increase in AIF nuclear translocation, but RPC ameliorated NAD
+
/NADH loss and blocked AIF nuclear translocation. MCAO in the rat induced AIF nuclear translocation in the ischemic penumbra after 24 h, which was ameliorated with RPC. We tested the hypothesis that RPC’s neuroprotection was instilled through long-term downregulation of nuclear PARP1 protein. RPC downregulated nuclear PARP1 protein for at least 6 days in PNCs, likely contributing to RPC’s ischemic tolerance. This study describes a novel mechanism by which RPC instills prophylaxis against ischemia-induced PARP1 overexpression and parthanatos, through a long-term reduction of nuclear PARP1 protein.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Cholinergic cells originating from the nuclei of the basal forebrain (BF) are critical for supporting various memory processes, yet BF cholinergic cell viability has not been explored in the context ...of focal cerebral ischemia. In the present study, we examined cell survival within several BF nuclei in rodents following transient middle cerebral artery occlusion. We tested the hypothesis that a previously established neuroprotective therapy-resveratrol preconditioning-would rescue BF cell loss, deficits in cholinergic-related memory performance, and hippocampal synaptic dysfunction after focal cerebral ischemia.
Adult (2-3-month old) male Sprague-Dawley rats or wild-type C57Bl/6J mice were injected intraperitoneally with a single dose of resveratrol or vehicle and subjected to transient middle cerebral artery occlusion using the intraluminal suture method 2 days later. Histopathological, behavioral, and electrophysiological outcomes were measured 1-week post-reperfusion. Animals with reduction in cerebral blood flow <30% of baseline were excluded.
Cholinergic cell loss was observed in the medial septal nucleus and diagonal band of Broca following transient middle cerebral artery occlusion. This effect was prevented by resveratrol preconditioning, which also ameliorated transient middle cerebral artery occlusion-induced deficits in cognitive performance and hippocampal long-term potentiation.
We demonstrate for the first time that focal cerebral ischemia induces cholinergic cell death within memory-relevant nuclei of the BF. The preservation of cholinergic cell viability may provide a mechanism by which resveratrol preconditioning improves memory performance and preserves functionality of memory-processing brain structures after focal cerebral ischemia.
A major concern for cardiac arrest (CA) survivors is the manifestation of long-term cognitive impairments. Physical exercise (PE) is a well-established approach to improve cognitive functions under ...certain pathological conditions. We previously showed that PE post-CA mitigates cognitive deficits, but the underlying mechanisms remain unknown. To define neuroprotective mechanisms, we analyzed whether PE post-CA protects neurons involved in memory. We first performed a contextual fear conditioning (CFC) test to confirm that PE post-CA preserves memory in rats. We then conducted a cell-count analysis and determined the number of live cells in the hippocampus, and septal and thalamic nuclei, all areas involved in cognitive functions. Lastly, we performed RNA-seq to determine PE post-CA effect on gene expression. Following CA, exercised rats had preserved CFC memory than sham PE animals. Despite this outcome, PE post-CA did not protect hippocampal cells from dying. However, PE ameliorated cell death in septal and thalamic nuclei compared to sham PE animals, suggesting that these nuclei are crucial in mitigating cognitive decline post-CA. Interestingly, PE affected regulation of genes related to neuroinflammation, plasticity, and cell death. These findings reveal potential mechanisms whereby PE post-CA preserves cognitive functions by protecting septal and thalamic cells via gene regulation.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Perturbations in synaptic function are major determinants of several neurological diseases and have been associated with cognitive impairments after cerebral ischemia (CI). Although the mechanisms ...underlying CI-induced synaptic dysfunction have not been well defined, evidence suggests that early hyperactivation of the actin-binding protein, cofilin, plays a role. Given that synaptic impairments manifest shortly after CI, prophylactic strategies may offer a better approach to prevent/mitigate synaptic damage following an ischemic event. Our laboratory has previously demonstrated that resveratrol preconditioning (RPC) promotes cerebral ischemic tolerance, with many groups highlighting beneficial effects of resveratrol treatment on synaptic and cognitive function in other neurological conditions. Herein, we hypothesized that RPC would mitigate hippocampal synaptic dysfunction and pathological cofilin hyperactivation in an ex vivo model of ischemia. Various electrophysiological parameters and synaptic-related protein expression changes were measured under normal and ischemic conditions utilizing acute hippocampal slices derived from adult male mice treated with resveratrol (10 mg/kg) or vehicle 48 h prior. Remarkably, RPC significantly increased the latency to anoxic depolarization, decreased cytosolic calcium accumulation, prevented aberrant increases in synaptic transmission, and rescued deficits in long-term potentiation following ischemia. Additionally, RPC upregulated the expression of the activity-regulated cytoskeleton associated protein, Arc, which was partially required for RPC-mediated attenuation of cofilin hyperactivation. Taken together, these findings support a role for RPC in mitigating CI-induced excitotoxicity, synaptic dysfunction, and pathological over-activation of cofilin. Our study provides further insight into mechanisms underlying RPC-mediated neuroprotection against CI and implicates RPC as a promising strategy to preserve synaptic function after ischemia.
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