*8.3. Brain Injury and Neuronal Diseases*

Substantial evidence has shown ketone bodies' pleiotropic neuroprotection properties due to their pivotal role in cerebral energy homeostasis and an active signaling molecule. BHB directly regulates inflammation and neurotrophic factors by inhibiting the activation of innate immune sensor NLRP3 and inhibiting HDAC, which upregulates BDNF (brain-derived neurotrophic factor) [90]. BDNF is crucial in the maintenance, restoration, and improvement of neural networks and brain functions after a brain injury. Thus, BDNF production in the brain plays an essential role in the prolonged maintenance of neuroplasticity [90]. Ketones have been known to have anti-seizure effects, which can be achieved through their action in altering synaptic neurotransmission via increasing GABA (gamma-aminobutyric acid) synthesis and decreasing glutamate synthesis [91]. Similarly, the anti-epileptic effects of ketones via activation of the KATP channels and GABA signaling lead to lower neuronal firing [92]. Multiple in vitro studies have demonstrated that ketones can increase the survival rate of cultured neocortical neurons and isolated

cortical mitochondria from exposure to hydrogen peroxide both with and without glucose addition [93]. It also reduced apoptosis after hypoxia in rat hippocampal neuron cultures from various insults, including hypoglycemia, hypoxia, and N-methyl-D-aspartate-induced excitotoxicity [93]. Furthermore, ketones demonstrated strong neuroprotective properties in various animal models of brain injury, reducing neuronal apoptosis and brain edema and enhancing sensory-motor and cognitive performance [89,93]. It has also reduced neuronal loss and infarct size in animal models of stroke and reduced the glutamate release and seizure severity in a mouse model of epilepsy [89,93]. In spinal cord injury models in rats, ketosis reduced spinal lesions enhanced the GLUT 1 and MCT1 vascular transporters, and forelimb motor function improvement [94]. Preclinical studies in adult rats with moderate and severe traumatic brain injury strongly demonstrated therapeutic actions, where it showed a significant reduction of infarct and penumbral volume in MRI, decreased tissue death and edema, and improved neurological scores [91]. The administration of ketones and hypertonic saline (HTS) showed beneficial effects in managing intracranial hypertonic pressure with enhanced cerebral metabolism [95]. Thus, the administration of exogenous ketones in patients with different stages of brain injury might benefit clinical outcomes due to the suggested neuroprotective property in maintaining mitochondrial function and decreasing inflammation, oxidative stress, and seizure problems [91]. Ketogenic interventions might facilitate the brain's utilization of ketones as an essential energy source and as a signaling molecule that may slow down the disease progression and delay or even prevent the disease onset if started earlier [96]. In vitro models of Parkinson's disease in mouse neuronal cultures demonstrated increased cell survival, enhanced mitochondrial membrane potential, and lower cytochrome c release, while a 60% increase in cell survival was also observed in human neuroblastoma cell culture [97]. Motor function was restored and prevented losing dopaminergic neurons after several infusions of sodium BHB (1.6 mmol/kg/day) [44]. Similarly, in the in vitro model of Alzheimer's disease, the cultured mouse hippocampal neurons were protected from amyloid beta 1 to 42 toxicity after 4 mmol/L ß-OHB was administered [44]. Ketone supplementation provided cognitive protection for several months [91] and even better performance in paragraph recall and Alzheimer's assessment scale tests in humans subjected to a ketogenic diet [97]. While in animal models of amyotrophic lateral sclerosis, the clinical and biological manifestations of the disease were beneficially altered after exposure to hyperketonemia, which had more remarkable motor neuron survival and enhanced motor function [98].
