Synaptic Activity and Bioenergy Homeostasis: Implications in Brain Trauma and Neurodegenerative Diseases

Abstract

Powered by glucose metabolism, the brain is the most energy-demanding organ in our body. Adequate ATP production and regulation of the metabolic processes are essential for the maintenance of synaptic transmission and neuronal function. Glutamatergic synaptic activity utilizes the largest portion of bioenergy for synaptic events including neurotransmitter synthesis, vesicle recycling, and most importantly, the postsynaptic activities leading to channel activation and rebalancing of ionic gradients. Bioenergy homeostasis is coupled with synaptic function via activities of the sodium pumps, glutamate transporters, glucose transport, and mitochondria translocation. Energy insufficiency is sensed by the AMP-activated protein kinase (AMPK), a master metabolic regulator that stimulates the catalytic process to enhance energy production. A decline in energy supply and a disruption in bioenergy homeostasis play a critical role in multiple neuropathological conditions including ischemia, stroke, and neurodegenerative diseases including Alzheimer’s disease and traumatic brain injuries.

Preliminary case control study to establish the correlation between novel peroxidation biomarkers in cord serum and the severity of hypoxic ischemic encephalopathy

“…However, case group patients exhibited a significantly lower cord pH, base excess, and Apgar scores as compared to patients from control group (P o0.001). Also, statistical significant differences were obtained for pCO 2 between both groups (Po 0.001).…”

“…Brain is strikingly dependent on aerobic metabolism to satisfy its elevated energy requirements and therefore, highly susceptible even to short periods of hypoxia [2]. Lack of oxygen causes exhaustion of ATP and accumulation of purine derivatives, especially hypoxanthine.…”

“…Brain cells are highly dependent on aerobic metabolism to obtain energy for ATP powered ion pumps, synaptic activity, and redox status. Intense hypoxia and re-oxygenation with high oxygen concentrations may lead to cell swelling, hyperexcitability and oxidative stress [2]. Altogether these circumstances may cause neuronal necrosis or activate pro-apoptotic pathways that lead to amplification of the initial damage evolving for hours, days or even weeks [3].…”

The Mitochondrial Complex V–Associated Large-Conductance Inner Membrane Current Is Regulated by Cyclosporine and Dexpramipexole

“…This suggests that a final common pathway for neuronal degeneration may be energy insufficiency, and an increased understanding of normal and pathologic mitochondrial metabolic regulation may provide significant insights into therapeutic approaches for the treatment of these diseases (Khatri and Man, 2013). The lack of compounds demonstrated to provide benefit in neurodegenerative disease has hampered this effort, inasmuch as a lack of tools has precluded effective experimental approaches.…”

Type 2 diabetes mellitus, drug addiction, bipolar disorder and epilepsy display overlapping aetiopathogenic mechanisms: Implication for prevention and pharmacotherapy

“…In selected cardiometabolic diseases (type 2 diabetes mellitus, metabolic syndrome, obesity, atherosclerosis) and neuropsychiatric diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease, epilepsy, bipolar spectrum disorder, depression, schizophrenia, primary headache, diabetic retinopathy, rett syndrome), the levels of brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are low Nousen et al, 2013). The neuronal glucose transporter (GLUT 3) and adenosine monophosphate-activated kinase (AMPK) are reduced in Alzheimer's disease (Khatri and Man, 2013). The energy sensor, AMPK, when activated by insulin sensitizers such as metformin + exenatide (Li, 2007) reduces oxidative stress, improves mitochondrial dysfunction, improves glucose uptake in Alzheimer's disease (AD) and slows down the main amloidogenic protein,Aβ, accumulation extracellularly and intracellularly or tau hyperphosphorylation intracellularly .…”