Hypoxia Ischemia

Oxygen and glucose deprivation in autism and role of calcium signalling

Neonatal hypoxia has been hypothesised to play an etiological role in development of autism. In animal models, hypoxia and hypoxic brain lesions are associated with some of autism-related neurobehavioral symptoms, including withdrawal in social and novel situations, diminished exploration in novel fields and repetitive behaviours [14985924, 16482712, 8075818].

Both acute and chronic oxygen and glucose deprivation lead to changes in membrane proteins, include excitation of chemoreceptors as well as vasoconstriction and systemic vasodilatation (see Cerebral_Blood_Flow). Hypoxia inhibits several potassium channels, leading to membrane depolarization and excessive calcium entry through LTCC, and subsequent downstream effects including release of calcium from intracellular pools, contributing further to cytosolic calcium overload. These events are thought to be G-protein linked [16828723]. Although a variety of membrane ion channels seem to be affected by hypoxic conditions, LTCC seem to be most significantly affected [14643931].

Neuronal damage during cerebral ischemia is thought to be mediated mainly through increases in intracellular calcium. The activation of LTCC and subsequently ryanodine-sensitive intracellular stores during oxygen and glucose deprivation plays a major role in these effects, which can be reduced in vitro by several calcium blocking agents [9445351, 10826535]. In addition, in several animal studies application of nimodipine resulted in prevention or reduction of adverse behavioural and neurochemical effects of perinatal hypoxia. In one study it was observed that nimodipine also enhanced the early postnatal development of calcium-binding proteins [8817697], while another study showed that alongside reducing negative behavioural consequences, nimodipine reduced adrenal dysfunction and abnormal corticosterone stress response in rats [8075818] (see Hormones). A study looking at energy metabolism in the developing brain damaged by aglycemic hypoxia found that calcium influx through LTCC mediated these effects. Application of diltiazem or verapamil but not nifedipine significantly improved the recovery from aglycemic hypoxia, manifested in decreased ATP energy state and increases in lactate [8897472] (see Mitochondria). Nimodipine and verapamil normalized cerebral pH following middle cerebral artery occlusion in another roden model of ischemia [3793803]. It has been suggested that the dual blockade of calcium entry using MK-801, a NMDA antagonist, alongside nimodipine may be a useful tool for protection against ischemic brain damage in clinical practice [1985301].

Upregulation of expression of several chemokine receptors of CNS and their activation has been observed following perinatal hypoxia and ischemia in animal models [16516309, 15467356] and absence of the chemokine receptor CCR2 protects mice against cerebral ischemia/reperfusion injury [17332467]. Both neuronal and glial cells possess a variety of chemokine receptors that can regulate calcium and other signaling pathways - in normal cirucumstances chemokine modulation of calcium homeostasis is believed to have positive effects on neuronal development, but excessive activation and expression of these receptors could have long term effects on their function and gene expression, as well as raise cellular vulnerability to viral and other proteins that act as chemokine receptor agonists (see Viruses). One of the pathways activated by chemokines is the calcium-mediated CREB (see Brain) [11958818].

It is worth noting in this context that hypoxia is thought to have a negative effect on the immune system – in addition to its modulating effects on various genes related to immune and inflammatory function observed in vitro [16849508], in vivo studies have further confirmed these findings – one example is the increased risk of infection by dysregulation of Th1/Th2 cytokine balance and decrease in T lympocyte numbers, as recorded in volunteers exposed to high altitudes [15870630]. On the other hand, the opposite mechanism has also been proposed, whereas fetal exposure to infection (see Viruses) and pro-inflammatory cytokines may reduce the threshold at which hypoxia becomes neurotoxic, and so make the brain more vulnerable to hypoxic insults [15707712].

It has been proposed that impairments of motor coordination following hypoxia might be the result of altered function of Purkinje neurons [16169666] (see Brain and Motor/Sensory). Perinatal anoxia has been observed to have negative effect on development and functioning of auditory systems, also closely linked to LTCC function [16365292] (see Auditory).

Periods of prolonged hypoxia are associated clinically with an increased incidence of dementia and raised suceptibility to development of neurological disorders like Alzheimer’s disease. It has been suggested recently that hypoxic channel up-regulation is dependent upon formation of amyloid beta peptides, which induce excessive activation of LTCC [16464656, 16321794, 12392105]. Blocking calcium channels by several antagonists has been shown to be neuroprotective in models of Alzheimer’s disease (see Related Disorders).

Amongst other types of cells the effect of hypoxia-induced dysregulations in calcium traffic through voltage gated channels in arteries may be of most relevance. A study looking at effect of hypoxia on lateral artery in striatum, a subcortical area of the brain, found substential gender difference in its vulnerability to hypoxia. Chemically induced hypoxia in rats lead to calcium overload and cell death, lesions, edema and immune activation. These effects and subsequent motor disurbances were highly sex-dependent and modulated by changes in hormonal levels, with males being much more susceptible than females (see Gender_Differences) [9678634].

In gastrointestinal tract, mucosal hypoxia is closely associated with chronic inflammation, and these events are dependent on alterations in the expression and function of CREB, whose phosphorylation is in great part regulated by calcium flux through LTCC [15253703] (see Gastrointestinal and Brain).

Lastly, LTCC are thought to mediate hypoxia-induced vasoconstrictive responses in human placenta, which could be completely abolished by a relatively low doses of nifedipine [16368136].