Vinpocetine enhance glucose uptake by brain neurons
Vinpocetine is a slightly altered form of vincamine, an alkaloid extracted from the Periwinkle plant, vinca minor. In use for almost 30 years, research has gradually shown vinpocetine to be the superior vinca alkaloid, having few and minor if any side effects, with a greater range of metabolic and clinical benefits than vincamine. Vinpocetine has been shown to be a cerebral metabolic enhancer and a selective cerebral vasodilator. Vinpocetine has been shown to enhance oxygen and glucose uptake from blood by brain neurons, and to increase neuronal ATP energy production. Both animal and human research has shown vinpocetine to restore impaired brain carbohydrate/energy metabolism.
Vinpocetine inhibits glutamate release induced by the convulsive agent 4-aminopyridine more potently than several antiepileptic drugs.
4-Aminopyridine (4-AP) is a convulsing agent that in vivo preferentially releases Glu, the most important excitatory amino acid neurotransmitter in the brain. Here the ionic dependence of 4-AP-induced Glu release and the effects of several of the most common antiepileptic drugs (AEDs) and of the new potential AED, vinpocetine on 4-AP-induced Glu release were characterized in hippocampus isolated nerve endings pre-loaded with labelled Glu ([3H]Glu). 4-AP-induced [3H]Glu release was composed by a tetrodotoxin (TTX) sensitive and external Ca2+ dependent fraction and a TTX insensitive fraction that was sensitive to the excitatory amino acid transporter inhibitor, TBOA. The AEDs: carbamazepine, phenytoin, lamotrigine and oxcarbazepine at the highest dose tested only reduced [3H]Glu release to 4-AP between 50-60%, and topiramate was ineffective. Vinpocetine at a much lower concentration than the above AEDs, abolished [3H]Glu release to 4-AP. We conclude that the decrease in [3H]Glu release linked to the direct blockade of presynaptic Na+ channels, may importantly contribute to the anticonvulsant actions of all the drugs tested here (except topiramate); and that the significantly greater vinpocetine effect in magnitude and potency on [3H]Glu release when excitability is exacerbated like during seizures, may involve the increase additionally exerted by vinpocetine in some K+ channels permeability.
Excitability linked to glutamate modulation is exacerbated by methamphetamine administration. Glutamate signaling plays a significant role in regards to DAergic deficits. Glutamate also contributes to the persistent deficits, as suggested by the inhibition of these deficits when NMDA antagonist are administered. Dopaminergic cells within the striatum possess AMPA and NMDA receptors. Glutamate-induced activation of these receptors promotes Ca 2+ influx into the DAergic neuron. This effect, when excessive, can result in mitochondrial damage and neurotoxicity.
Reversing brain damage in former NFL players: implications for traumatic brain injury and substance abuse rehabilitation.
Brain injuries are common in professional American football players. Finding effective rehabilitation strategies can have widespread implications not only for retired players but also for patients with traumatic brain injury and substance abuse problems. An open label pragmatic clinical intervention was conducted in an outpatient neuropsychiatric clinic with 30 retired NFL players who demonstrated brain damage and cognitive impairment. The study included weight loss (if appropriate); fish oil (5.6 grams a day); a high-potency multiple vitamin; and a formulated brain enhancement supplement that included nutrients to enhance blood flow (ginkgo and vinpocetine), acetylcholine (acetyl-l-carnitine and huperzine A), and antioxidant activity (alpha-lipoic acid and n-acetyl-cysteine). The trial average was six months. Outcome measures were Microcog Assessment of Cognitive Functioning and brain SPECT imaging. In the retest situation, corrected for practice effect, there were statistically significant increases in scores of attention, memory, reasoning, information processing speed and accuracy on the Microcog. The brain SPECT scans, as a group, showed increased brain perfusion, especially in the prefrontal cortex, parietal lobes, occipital lobes, anterior cingulate gyrus and cerebellum. This study demonstrates that cognitive and cerebral blood flow improvements are possible in this group with multiple interventions.
Vinpocetine impact on blood flow may decrease BBB permeability. Significant increases in blood pressure is often experienced post-admisnistration. Vasodilatation and (PDE) type-1 inhibition may cause the effect on smooth muscle tissue.
Glucose Regulation
Glucose is the principal brain fuel. Most other cells and organs of the body are able to "burn" fat as well as glucose to produce ATP bioenergy, but brain neurons can only burn glucose under normal, non-starvation/ketogenic conditions. The brain is only 2% of the body mass, yet typically consumes 15-20% of total body ATP energy. The brain is dependent on a second-by-second delivery of glucose from the bloodstream, as neurons can only store about a 2-minute supply of glucose (as glycogen) at any given time. The brain must have access to a large portion of the glucose flowing through the bloodstream.
Unlike most other body tissues, the brain does not require insulin to absorb glucose from the blood. The effect of insulin on the brain is less well defined. Elevations of circulating insulin can alter brain function, augmenting the counterregulatory response to hypoglycemia, altering feeding behavior. Thus, the optimal blood status for the brain to acquire its disproportionately large share of blood sugar is a normal blood sugar level, combined with low blood insulin. When insulin is low or absent in the bloodstream, the rest of the body will ignore the blood sugar and burn fat or amino acids for their fuel.
Methamphetamine is known to stimulate production of insulin, leaving the brain with less then adequate amount of glucose. This will cause a rapid glucose uptake by almost all body tissues, leaving far less than optimal supplies for the brain.
Methamphetamine-induced insulin release.
Administration of methamphetamine or amphetamine to rats and mice produces a rapid increase in the level of immunoassayable plasma insulin not attributable to hyperglycemia. While in the mouse this release of insulin is followed consistently by a profound hypoglycemia, in the rat this response is variable. Studies in vitro demonstrate that insulin is released by a direct effect of methamphetamine on the pancreas.
Profound hypoglycemia is observed in the human subjects as well
Physiologic response to hypoglycemia
The physiologic response to hypoglycemia is a complex and well-coordinated process. In healthy humans, there is an ordered, failsafe response system that begins with a reduction in insulin secretion while blood glucose concentration is still in the physiologic range. As blood glucose concentration declines further, peripheral and central glucose sensors relay this information to central integrative centers to coordinate the secretion of counterregulatory hormones (glucagon, epinephrine, norepinephrine, growth hormone and cortisol, respectively) and avert the progression of hypoglycemia. Type 1 diabetes perturbs these counterregulatory responses: circulating insulin levels cannot be reduced (due to exogenous insulin); glucagon secretion is blunted or absent; and epinephrine secretion is blunted and shifted to a lower plasma glucose concentration. It is also observed in methamphetamine induced hyperinsulinemia.
Counterregulation has also been shown to be impaired in type 2 diabetes. In this setting, the glucagon response to hypoglycemia may be normal or blunted, while epinephrine response remains intact, if not augmented. Patients affected by type 1 and type 2 diabetes can develop the syndrome of hypoglycemia unawareness.
Hypoglycemia unawareness develops as recurrent iatrogenic hypoglycemia shifts the glycemic threshold for counterregulation and development of hypoglycemic symptoms to lower plasma glucose concentrations. In this setting, neurogenic symptoms, which are usually the initial warning symptoms of hypoglycemia, are blunted and the first manifestation of hypoglycemia becomes neuroglycopenia. The mechanisms underlying the development of hypoglycemia unawareness may be related to both altered central sensing of hypoglycemia and impaired coordination of responses to hypoglycemia. Neuroglycopenia is a medical term that refers to a shortage of glucose (glycopenia) in the brain, usually due to hypoglycemia. Glycopenia affects the function of neurons, and alters brain function and behavior.
Signs and symptoms of neuroglycopenia
Abnormal mentation, impaired judgement
Nonspecific dysphoria, anxiety, moodiness, depression, crying, fear of dying, suicidal thoughts
Negativism, irritability, belligerence, combativeness, rage
Personality change, emotional lability
Fatigue, weakness, apathy, lethargy, daydreaming, sleep
Confusion, amnesia, dizziness, delirium
Staring, "glassy" look, blurred vision, double vision
Automatic behavior
Difficulty speaking, slurred speech
Ataxia, incoordination, sometimes mistaken for "drunkenness"
Focal or general motor deficit, paralysis, hemiparesis
Paresthesia, headache
Stupor, coma, abnormal breathing
Generalized or focal seizures
Not all of the above manifestations occur in every case of hypoglycemia. There is no consistent order to the appearance of the symptoms. Specific manifestations vary by age and by the severity of the hypoglycemia. In older children and adults, moderately severe hypoglycemia can resemble mania, mental illness, drug intoxication, or drunkenness. In the elderly, hypoglycemia can produce focal stroke-like effects or a hard-to-define malaise. The symptoms of a single person do tend to be similar from episode to episode.
Most neurons have the ability to use other fuels besides glucose (e.g., lactic acid, ketones). Our knowledge of the "switchover" process is incomplete. The most severe neuroglycopenic symptoms occur with hypoglycemia caused by excess insulin because insulin reduces the availability of other fuels by suppressing ketogenesis and gluconeogenesis.
A few types of specialized neurons, especially in the hypothalamus, act as glucose sensors, responding to changing levels of glucose by increasing or decreasing their firing rates. They can elicit a variety of hormonal, autonomic, and behavioral responses to neuroglycopenia. The hormonal and autonomic responses include release of counterregulatory hormones. There is some evidence that the autonomic nervous system can alter liver glucose metabolism independently of the counterregulatory hormones.
Compensatory responses to neuroglycopenia
Adjustment of efficiency of transfer of glucose from blood across the blood–brain barrier into the central nervous system represents a third form of compensation which occurs more gradually. Levels of glucose within the central nervous system are normally lower than the blood, regulated by an incompletely understood transfer process. Chronic hypoglycemia or hyperglycemia seems to result in an increase or decrease in efficiency of transfer to maintain CNS levels of glucose within an optimal range.
Neuroglycopenia without hypoglycemia
In both young and old patients, the brain may habituate to low glucose levels, with a reduction of noticeable symptoms, sometimes despite neuroglycopenic impairment. In insulin-dependent diabetic patients this phenomenon is termed hypoglycemia unawareness and is a significant clinical problem when improved glycemic control inefficient. Frequent in methamphetamine user, neuroglycopenia is observed after repeated hypoglycemic episode.
