Inflammation-Mediated Memory Dysfunction and Effects of a Ketogenic Diet in a Murine Model of Multiple Sclerosis

Abstract

A prominent clinical symptom in multiple sclerosis (MS), a progressive disorder of the central nervous system (CNS) due to heightened neuro-inflammation, is learning and memory dysfunction. Here, we investigated the effects of a ketogenic diet (KD) on memory impairment and CNS-inflammation in a murine model of experimental autoimmune encephalomyelitis (EAE), using electrophysiological, behavioral, biochemical and in vivo imaging approaches. Behavioral spatial learning deficits were associated with motor disability in EAE mice, and were observed concurrently with brain inflammation. The KD improved motor disability in the EAE model, as well as CA1 hippocampal synaptic plasticity (long-term potentiation) and spatial learning and memory (assessed with the Morris Water Maze). Moreover, hippocampal atrophy and periventricular lesions in EAE mice were reversed in KD-treated EAE mice. Finally, we found that the increased expression of inflammatory cytokines and chemokines, as well as the production of reactive oxygen species (ROS), in our EAE model were both suppressed by the KD. Collectively, our findings indicate that brain inflammation in EAE mice is associated with impaired spatial learning and memory function, and that KD treatment can exert protective effects, likely via attenuation of the robust immune response and increased oxidative stress seen in these animals.

In VivoImaging of Reactive Oxygen Species in Mouse Brain by using [3H]Hydromethidine as a Potential Radical Trapping Radiotracer

“…It has also been reported to detect O 2 • − production in the hippocampus of lithium-pilocarpine epilepsy rats, 17 beta cells of type II diabetes mellitus rats, 18 or the brain of multiple sclerosis mice. 19 Recently, Hall et al 20 have reported the detection of O 2…”

Synaptic plasticity in multiple sclerosis and in experimental autoimmune encephalomyelitis

“…Ziehn et al [53] found normal LTP at CA1 hippocampal synapses but impaired basal excitatory synaptic transmission and paired-pulse facilitation (PPF) (a presynaptic form of synaptic plasticity) at 21-45 days after induction of EAE. By contrast, two subsequent studies showed that LTP was impaired at two different time points (14-19 days and 30-35 days) after EAE induction [54,55], while excitatory basal transmission and PPF were unaltered in the acute phase of disease [55]. In the latter study, the LTP deficit was associated with a decreased expression of the NMDA receptor subunit NR2B and increased interleukin-1b (IL-1b) levels.…”

“…In the latter study, the LTP deficit was associated with a decreased expression of the NMDA receptor subunit NR2B and increased interleukin-1b (IL-1b) levels. Interestingly, a ketogenic diet could rescue motor disability, spatial learning and LTP impairment associated with EAE by restraining pro-inflammatory cytokines and oxidative stress [54]. Our group has recently performed a comprehensive study of bidirectional synaptic plasticity at CA3-CA1 synapses from EAE (20-25 days after disease induction) compared to their respective complete Freund's adjuvant (CFA) controls [17].…”

Ketosis as a treatment for multiple metabolic and neurodegenerative pathologies

“…Transgenic animal models of neurodegenerative diseases showed positive outcomes induced by ketogenic diet. Increased motor neuron number was reported in ALS transgenic models in response to ketosis (Zhao et al 2006;Zhao et al 2012), reduced lesion volume was described after TBI [50], increased cell survival and decreased seizure frequency in kainate-induced seizure models were observed [51] and suppressed inflammatory cytokines and chemokines in an experimental model of multiple sclerosis was reported [52].…”