Optimal levels of unsaturated fatty acids have positive impacts on the use of prolonged bouts of ... more Optimal levels of unsaturated fatty acids have positive impacts on the use of prolonged bouts of hypothermia in mammalian hibernators, which generally have to face low winter ambient temperatures. Unsaturated fatty acids can maintain the fluidity of fat and membrane phospholipids at low body temperatures. However, less attention has been paid to their role in the regulation of shallow hypothermia, and in tropical species, which may be challenged more by seasonal energetic and/or water shortages than by low temperatures. The present study assessed the relationship between the fatty acids content of white adipose and liver tissues and the expression of shallow hypothermia in a tropical heterothermic primate, the gray mouse lemur (Microcebus murinus). The adipose tissue is the main tissue for fat storage and the liver is involved in lipid metabolism, so both tissues were expected to influence hypothermia dependence on fatty acids. As mouse lemurs largely avoid deep hypothermia (i.e. to...
Changes in the metabolism of polyunsaturated fatty acids (PUFA), both in children on the high fat... more Changes in the metabolism of polyunsaturated fatty acids (PUFA), both in children on the high fat ketogenic diet (KD) for seizure control and in rats on a KD enriched in PUFA, raise the possibility that increased brain arachidonic acid (ARA) and/or docosahexaenoic acid (DHA) may contribute to better seizure control. Our studies with PUFA and several other reports raise the question of whether persistent ketonemia or elevated brain uptake of ketones are strictly necessary for the clinical effectiveness of the KD in intractable epilepsy. To address this question, we have developed the synthesis of carbon-11 labeled acetoacetate ((11)C-AcAc) for PET studies to investigate brain ketone uptake directly in humans and animals. In rats on the KD for 10 days, (11)C-AcAc uptake by the brain increased 7- to 8-fold, an increase similar to that induced by 48 h fasting. In rats and humans, paired PET scans ((11)C-AcAc followed immediately by(18)fluorodeoxyglucose) will be conducted to assess the uptake of AcAc and glucose by the brain while on the KD and in neurological disorders associated with aging.
Different kinds of challenge can alter spontaneous ongoing electroencephalographic (EEG) rhythms ... more Different kinds of challenge can alter spontaneous ongoing electroencephalographic (EEG) rhythms in animal models, thus providing paradigms to evaluate treatment effects in drug discovery. The effects of challenges represented by pharmacological agents, hypoxia, sleep deprivation and transcranial magnetic stimulation (TMS) on EEG rhythms are here reviewed to build a knowledge platform for innovative translational models for drug discovery in Alzheimer's disease (AD). It has been reported that antagonists of cholinergic neurotransmission cause synchronisation of spontaneous ongoing EEG rhythms in terms of enhanced power of EEG low frequencies and decreased power of EEG high frequencies. Acetylcholinesterase inhibitors and serotonergic drugs may restore a normal pattern of EEG desynchronisation. Sleep deprivation and hypoxia challenges have also been reported to elicit abnormal synchronisation of spontaneous ongoing EEG rhythms in rodents. The feasibility and reproducibility of TMS have been demonstrated in rodents but information on a consistent modulation of EEG after TMS manipulation is very limited. Transgenic mice over-expressing human amyloid precursor protein complementary DNAs (cDNAs) harbouring the 'Swedish' mutation and PS-1 cDNAs harbouring the A264E mutation, which recapitulate some of the pathological features of AD, exhibit alterations of spontaneous ongoing EEG rhythms at several low and high frequencies. This does not appear, however, to be a consequence of beta-amyloid deposition in the brain. The present review provides a critical evaluation of changes of spontaneous ongoing EEG rhythms due to the experimental manipulations described above, in order to stimulate the promote more adherent models fitting dynamics in humans.
Normally, the brain&a... more Normally, the brain's fuel is glucose, but during fasting it increasingly relies on ketones (beta-hydroxybutyrate, acetoacetate, and acetone) produced in liver mitochondria from fatty acid beta-oxidation. Although moderately raised blood ketones produced on a very high fat ketogenic diet have important clinical effects on the brain, including reducing seizures, ketone metabolism by the brain is still poorly understood. The aim of the present work was to assess brain uptake of carbon-11-labeled acetoacetate (11C-acetoacetate) by positron emission tomography (PET) imaging in the intact, living rat. To vary plasma ketones, we used three dietary conditions: high carbohydrate control diet (low plasma ketones), fat-rich ketogenic diet (raised plasma ketones), and 48-h fasting (raised plasma ketones). 11C-acetoacetate metabolism was measured in the brain, heart, and tissue in the mouth area. Using 11C-acetoacetate and small animal PET imaging, we have noninvasively quantified an approximately seven- to eightfold enhanced brain uptake of ketones on a ketogenic diet or during fasting. This opens up an opportunity to study brain ketone metabolism in humans.
Optimal levels of unsaturated fatty acids have positive impacts on the use of prolonged bouts of ... more Optimal levels of unsaturated fatty acids have positive impacts on the use of prolonged bouts of hypothermia in mammalian hibernators, which generally have to face low winter ambient temperatures. Unsaturated fatty acids can maintain the fluidity of fat and membrane phospholipids at low body temperatures. However, less attention has been paid to their role in the regulation of shallow hypothermia, and in tropical species, which may be challenged more by seasonal energetic and/or water shortages than by low temperatures. The present study assessed the relationship between the fatty acids content of white adipose and liver tissues and the expression of shallow hypothermia in a tropical heterothermic primate, the gray mouse lemur (Microcebus murinus). The adipose tissue is the main tissue for fat storage and the liver is involved in lipid metabolism, so both tissues were expected to influence hypothermia dependence on fatty acids. As mouse lemurs largely avoid deep hypothermia (i.e. to...
Optimal levels of unsaturated fatty acids have positive impacts on the use of prolonged bouts of ... more Optimal levels of unsaturated fatty acids have positive impacts on the use of prolonged bouts of hypothermia in mammalian hibernators, which generally have to face low winter ambient temperatures. Unsaturated fatty acids can maintain the fluidity of fat and membrane phospholipids at low body temperatures. However, less attention has been paid to their role in the regulation of shallow hypothermia, and in tropical species, which may be challenged more by seasonal energetic and/or water shortages than by low temperatures. The present study assessed the relationship between the fatty acids content of white adipose and liver tissues and the expression of shallow hypothermia in a tropical heterothermic primate, the gray mouse lemur (Microcebus murinus). The adipose tissue is the main tissue for fat storage and the liver is involved in lipid metabolism, so both tissues were expected to influence hypothermia dependence on fatty acids. As mouse lemurs largely avoid deep hypothermia (i.e. to...
Changes in the metabolism of polyunsaturated fatty acids (PUFA), both in children on the high fat... more Changes in the metabolism of polyunsaturated fatty acids (PUFA), both in children on the high fat ketogenic diet (KD) for seizure control and in rats on a KD enriched in PUFA, raise the possibility that increased brain arachidonic acid (ARA) and/or docosahexaenoic acid (DHA) may contribute to better seizure control. Our studies with PUFA and several other reports raise the question of whether persistent ketonemia or elevated brain uptake of ketones are strictly necessary for the clinical effectiveness of the KD in intractable epilepsy. To address this question, we have developed the synthesis of carbon-11 labeled acetoacetate ((11)C-AcAc) for PET studies to investigate brain ketone uptake directly in humans and animals. In rats on the KD for 10 days, (11)C-AcAc uptake by the brain increased 7- to 8-fold, an increase similar to that induced by 48 h fasting. In rats and humans, paired PET scans ((11)C-AcAc followed immediately by(18)fluorodeoxyglucose) will be conducted to assess the uptake of AcAc and glucose by the brain while on the KD and in neurological disorders associated with aging.
Different kinds of challenge can alter spontaneous ongoing electroencephalographic (EEG) rhythms ... more Different kinds of challenge can alter spontaneous ongoing electroencephalographic (EEG) rhythms in animal models, thus providing paradigms to evaluate treatment effects in drug discovery. The effects of challenges represented by pharmacological agents, hypoxia, sleep deprivation and transcranial magnetic stimulation (TMS) on EEG rhythms are here reviewed to build a knowledge platform for innovative translational models for drug discovery in Alzheimer's disease (AD). It has been reported that antagonists of cholinergic neurotransmission cause synchronisation of spontaneous ongoing EEG rhythms in terms of enhanced power of EEG low frequencies and decreased power of EEG high frequencies. Acetylcholinesterase inhibitors and serotonergic drugs may restore a normal pattern of EEG desynchronisation. Sleep deprivation and hypoxia challenges have also been reported to elicit abnormal synchronisation of spontaneous ongoing EEG rhythms in rodents. The feasibility and reproducibility of TMS have been demonstrated in rodents but information on a consistent modulation of EEG after TMS manipulation is very limited. Transgenic mice over-expressing human amyloid precursor protein complementary DNAs (cDNAs) harbouring the 'Swedish' mutation and PS-1 cDNAs harbouring the A264E mutation, which recapitulate some of the pathological features of AD, exhibit alterations of spontaneous ongoing EEG rhythms at several low and high frequencies. This does not appear, however, to be a consequence of beta-amyloid deposition in the brain. The present review provides a critical evaluation of changes of spontaneous ongoing EEG rhythms due to the experimental manipulations described above, in order to stimulate the promote more adherent models fitting dynamics in humans.
Normally, the brain&a... more Normally, the brain's fuel is glucose, but during fasting it increasingly relies on ketones (beta-hydroxybutyrate, acetoacetate, and acetone) produced in liver mitochondria from fatty acid beta-oxidation. Although moderately raised blood ketones produced on a very high fat ketogenic diet have important clinical effects on the brain, including reducing seizures, ketone metabolism by the brain is still poorly understood. The aim of the present work was to assess brain uptake of carbon-11-labeled acetoacetate (11C-acetoacetate) by positron emission tomography (PET) imaging in the intact, living rat. To vary plasma ketones, we used three dietary conditions: high carbohydrate control diet (low plasma ketones), fat-rich ketogenic diet (raised plasma ketones), and 48-h fasting (raised plasma ketones). 11C-acetoacetate metabolism was measured in the brain, heart, and tissue in the mouth area. Using 11C-acetoacetate and small animal PET imaging, we have noninvasively quantified an approximately seven- to eightfold enhanced brain uptake of ketones on a ketogenic diet or during fasting. This opens up an opportunity to study brain ketone metabolism in humans.
Optimal levels of unsaturated fatty acids have positive impacts on the use of prolonged bouts of ... more Optimal levels of unsaturated fatty acids have positive impacts on the use of prolonged bouts of hypothermia in mammalian hibernators, which generally have to face low winter ambient temperatures. Unsaturated fatty acids can maintain the fluidity of fat and membrane phospholipids at low body temperatures. However, less attention has been paid to their role in the regulation of shallow hypothermia, and in tropical species, which may be challenged more by seasonal energetic and/or water shortages than by low temperatures. The present study assessed the relationship between the fatty acids content of white adipose and liver tissues and the expression of shallow hypothermia in a tropical heterothermic primate, the gray mouse lemur (Microcebus murinus). The adipose tissue is the main tissue for fat storage and the liver is involved in lipid metabolism, so both tissues were expected to influence hypothermia dependence on fatty acids. As mouse lemurs largely avoid deep hypothermia (i.e. to...
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Papers by Fabien Pifferi