Primary hypersomnias of central origin.

PURPOSE OF REVIEW: This review discusses the various causes of primary hypersomnias with emphasis on clinical recognition, diagnosis, and treatment options. RECENT FINDINGS: Narcolepsy is probably the most fascinating syndrome causing excessive daytime sleepiness. With increasing understanding of the hypocretin/orexin pathways and the neurotransmitters that subserve the role of wakefulness and sleep, newer therapeutic modalities with promising results are being investigated and opening new frontiers in the treatment of this rare but devastating disease. SUMMARY: This article reviews the primary hypersomnias of central origin. Where possible, clinical cases that highlight and explain the clinical syndromes are included. Treatment modalities and future directions are also discussed to help the clinician identify and treat the underlying disorder.

Neurogenic pathway mediated remote preconditioning protects the brain from transient focal ischemic injury.

Attenuation of ischemic injury can be achieved by priming the brain with a sub-lethal ischemic insult, a phenomenon known as ischemic preconditioning (IP). We sought to determine if subjecting a distant organ, such as the lower limb, to a similar priming ischemic insult would result in protection of the brain from a subsequent severe ischemic injury, as induced by middle cerebral artery occlusion (MCAo) and if this protection is mediated via a neurogenic pathway. Adult Wistar male rats were subjected to either remote preconditioning (RPC) or sham surgery and then subsequently underwent 2 h MCAo 24, 48 or 72 h after the RPC/sham RPC stimulus. Of the animals undergoing RPC, only those that sustained MCAo 24 h later showed significantly smaller cerebral infarct volumes (150.34±30.91 mm(3)) and better clinical neurological outcomes (1.15±0.69) as compared to the sham RPC group (infarct volume 250.25±26.98mm(3); neurological score 1.80±0.87) (P<0.05). RPC animals sustaining MCAo at 48 and 72 h later did not show significant differences in cerebral infarct volumes or clinical neurological outcomes as compared to the sham RPC group. Furthermore, attenuation of the neuroprotective effect by the ganglion blocker hexamethonium suggested a neurogenically mediated pathway responsible for this phenomenon. Remote sub-lethal ischemic injury to both lower limbs results in cerebral protection from subsequent ischemia within 24 h of initiation of the RPC stimulus and this protection in part may be mediated via a neurogenic pathway.

Harmful effect of kainic acid on brain ischemic damage is not related to duration of status epilepticus.

Status epilepticus is common in infants and may have long-term consequences on the brain persisting into adulthood. Vascular ischemia is a common cause of stroke in adulthood. The extent of stroke in 15-day-old rats is larger when previously exposed to kainic acid-induced status epilepticus. In this paper, we assess whether shortening the duration of seizures modifies subsequent susceptibility to middle cerebral artery occlusion. We administered pentobarbital 50 mg/kg to abort seizures after 1 h. Although administration of pentobarbital aborted seizures, it had no effect on volume of infarction following ischemia. This study indicates that there is dissociation between stopping status epilepticus and modifying its long-term consequences.

Antithrombotic and thrombolytic therapy for ischemic stroke.

Thrombolytic and antithrombotic agents form the cornerstone of stroke treatment and prevention. Recombinant tissue plasminogen activation (rt-PA) improves the outcome in patients treated within 3 hours of stroke onset. The risk-benefit ratio is narrow because of an increased risk for bleeding, but studies do not support a higher risk in the geriatric population. Emerging trials are directed at extending the therapeutic window and identifying agents that could provide better safety profiles. Large randomized trials have also highlighted the effectiveness and safety of early and continuous antiplatelet therapy in reducing atherothrombotic stroke recurrence. Aspirin has become the antiplatelet treatment standard against which several other antiplatelet agents have been shown to be more effective. The prevention of cardioembolic stroke is best accomplished with oral anticoagulation, barring any contraindications.

Caveolin-1 deficiency increases cerebral ischemic injury.

Caveolins (Cav), the principal structural proteins of the caveolar domains, have been implicated in the pathogenesis of ischemic injury. Indeed, changes in caveolin expression and localization have been reported in renal and myocardial ischemia. Genetic ablation of the Cav-1 gene in mice was further shown to increase the extent of ischemic injury in a model of hindlimb ischemia. However, the role of Cav-1 in the pathogenesis of cerebral ischemia remains unknown. Immunoblot and immunofluorescence analyses of rat brains subjected to middle cerebral artery occlusion revealed marked increases in endothelial Cav-1 and Cav-2 protein levels. To directly assess the functional role of caveolins in the pathogenesis of cerebral ischemic injury, we next investigated the effects of cerebral ischemia in caveolin knockout (KO) mice. Interestingly, Cav-1 KO mice showed a marked increase of cerebral volume of infarction, as compared with wild-type and Cav-2 KO mice. Immunofluorescence analyses showed an increased number of proliferating endothelial cells in wild-type ischemic brains, as compared with Cav-1 KO ischemic brains. Immunoblot analyses of wild-type ischemic brains showed an increase in endothelial nitric oxide synthase protein levels. Conversely, the protein levels of endothelial nitric oxide synthase remained unchanged in Cav-1 KO ischemic brains. TUNEL analysis also showed increased apoptotic cell death in Cav-1 KO ischemic brains, as compared with wild-type ischemic brains. Our findings indicate cerebral ischemia induces a marked increase in endothelial Cav-1 and Cav-2 protein levels. Importantly, genetic ablation of the Cav-1 gene in mice results in increased cerebral volume of infarction. Mechanistically, Cav-1 KO ischemic brains showed impaired angiogenesis and increased apoptotic cell death.

EDG receptors as a potential therapeutic target in retinal ischemia-reperfusion injury.

LPA (lysophosphatidic acid) specific endothelial differentiation gene (EDG) receptors have been implicated in various anti-apoptotic pathways. Ischemia of the brain and retina causes neuronal apoptosis, which raises the possibility that EDG receptors participate in anti-apoptotic signaling in ischemic injury. We examined the expression of EDG receptors in a model of retinal ischemia-reperfusion injury and also tested LXR-1035, a novel analogue of LPA, in the rat following global retinal ischemic injury. Rats were subjected to 45 or 60 min of raised intraocular pressure. Animals were sacrificed at 24 h post-ischemia and retinal tissue was stained for EDG receptors. In separate experiments, animals were randomized to receive LXR or saline vehicle by intravitreal injection 24 h prior to ischemia. The degree of retinal damage was assessed morphologically by measuring the thickness of the inner retinal layers as well as functionally by electroretinography (ERG). We found that the normal retina has a baseline expression of the LPA receptors, EDG-2 and EDG-4, which are significantly upregulated in the inner layers in response to ischemia. Animals pretreated with LXR-1035 had dose-dependent, significant reductions in histopathologic damage and significant improvement in functional deficits compared with corresponding vehicle-controls, after 45 and 60 min of ischemia. These results suggest that LPA receptor signaling may play an important role in neuroprotection in retinal ischemia-reperfusion injury.

Antithrombotic and thrombolytic therapy for ischemic stroke.

Thrombolytic and antithrombotic agents form the cornerstone of stroke treatment and prevention. Recombinant tissue plasminogen activator improves outcome in patients treated within 3 hours of stroke onset. Emerging trials are directed to extend the therapeutic window and identify agents that could provide better safety profiles. Large, randomized trials have also highlighted the effectiveness and safety of early and continuous antiplatelet therapy in reducing atherothrombotic stroke recurrence. Aspirin has become the antiplatelet treatment standard against which several other antiplatelet agents have been shown to be more effective. The prevention of cardioembolic stroke is best accomplished with oral anticoagulation, barring any contraindications.

Ischemic preconditioning is mediated by erythropoietin through PI-3 kinase signaling in an animal model of transient ischemic attack.

Ischemic preconditioning (IP) protects the brain from subsequent, prolonged, and lethal ischemia in experimental studies. Erythropoietin (EPO) participates in the brain's intrinsic response to injury and may play a role in preconditioning. By using a middle cerebral artery occlusion (MCAo) model of transient ischemic attack (TIA), we sought to determine whether EPO is required for IP in the protective response against focal ischemic stroke. Rats underwent three 10-min MCA occlusions or sham surgery. Three days later, animals underwent 2 hr of MCAo and 22 hr of reperfusion. Experimental TIAs reduced infarct volumes by 55% (P < 0.05), inhibited DNA fragmentation, and improved neurological outcome by 50% (P < 0.05) after ischemic stroke. EPO and its receptor were up-regulated by IP in the ipsilateral hemisphere by 24 hr after IP, before ischemic stroke and soluble EPO receptor attenuated neuroprotection by IP (88% reduction, P < 0.05). Pretreatment with the PI-3 kinase inhibitor wortmannin abolished the protective effect of IP against ischemic injury (P < 0.05). IP may be mediated in part by EPO through a PI-3 kinase pathway.

Effects of status epilepticus early in life on susceptibility to ischemic injury in adulthood.

PURPOSE: Status epilepticus (SE) commonly occurs in children, whereas ischemic stroke is the most frequent neurologic insult in adults. The purpose of this study was to determine the effect of SE induced in immature (15 days old; PN15) male rats, on susceptibility to subsequent transient focal cerebral ischemia induced in adulthood. METHODS: SE was induced by flurothyl ether (FE) or kainic acid (KA). Rats that did not develop seizures after FE or KA served as controls. Five weeks later, the now-adult rats were subjected to middle cerebral artery occlusion (MCAo) for 1 or 2 h by using the intraluminal filament technique. The extent of the infarct volume was evaluated 24 h later. RESULTS: In rats submitted to 1-h-long FE-SE, the volume of infarction was significantly reduced compared with that in rats exposed to FE without SE. Longer duration of FE-SE was acutely lethal. KA-SE induced prolonged behavioral SE (156 +/- 17.5 min). In these rats, the volume of infarction was significantly larger compared with that in rats that did not show any electrographic seizures after KA administration. Comparison of FE and KA groups revealed that differences in the size of infarction were confined into cortical areas served by the MCA. Neither type of SE induced any obvious histologic changes in these neocortical regions before stroke induction. CONCLUSIONS: Early in life, SE can influence the outcome of a subsequent focal ischemic insult in adulthood. The extent of the infarct is related to the duration and cause of SE. Prolonged SE induced by KA worsens the outcome, whereas FE-SE has a neuroprotective effect.

Erythropoietin (epoetin) as a protective factor for the brain.

Erythropoietin (EPO) has been viewed traditionally as a hematopoietic cytokine. Emerging evidence now exists supporting a physiologic role for EPO within the nervous system. EPO is expressed in the developing central nervous system and is capable of regulating the production of neuronal progenitor cells. There are numerous preclinical studies demonstrating a neuroprotective potential for EPO in a variety of disorders of both the central and peripheral nervous systems. A small pilot study in patients with acute ischemic stroke has recently been completed and the results are encouraging. Its mechanism of action is multifactorial but probably related to its ability to act as an antiapoptotic agent. Its widespread use clinically for the treatment of anemias has given us the experience and knowledge of its safety and pharmacokinetics. EPO is thus an ideal compound to study for the potential treatment of a variety of neurologic disorders.

Cell transplants offer promise for stroke recovery.

Cell transplantation is an experimental approach to restore brain function in neurodegenerative disorders such as Parkinson's and Huntington's disease. Transplantation also represents a possible strategy to repair the brain after a stroke. Various cell types are under investigation in experimental stroke studies. This review discusses the different graft sources and presents preliminary data on the transplantation of neural progenitor cells after stroke in rats. Following transplantation, progenitor cells proliferated and differentiated into all the different brain cell types, including neurons, and they repopulated the ischemic infarct. These results suggest that cell transplantation may serve as a future restorative therapy for stroke and other neurologic disorders such as Parkinson's disease, Alzheimer's disease, trauma, and multiple sclerosis.

Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury.

Erythropoietin (EPO) plays an important role in the brain's response to neuronal injury. Systemic administration of recombinant human EPO (rhEPO) protects neurons from injury after middle cerebral artery occlusion, traumatic brain injury, neuroinflammation, and excitotoxicity. Protection is in part mediated by antiapoptotic mechanisms. We conducted parallel studies of rhEPO in a model of transient global retinal ischemia induced by raising intraocular pressure, which is a clinically relevant model for retinal diseases. We observed abundant expression of EPO receptor (EPO-R) throughout the ischemic retina. Neutralization of endogenous EPO with soluble EPO-R exacerbated ischemic injury, which supports a crucial role for an endogenous EPO/EPO-R system in the survival and recovery of neurons after an ischemic insult. Systemic administration of rhEPO before or immediately after retinal ischemia not only reduced histopathological damage but also promoted functional recovery as assessed by electroretinography. Exogenous EPO also significantly diminished terminal deoxynucleotidyltransferase-mediated dUTP end labeling labeling of neurons in the ischemic retina, implying an antiapoptotic mechanism of action. These results further establish EPO as a neuroprotective agent in acute neuronal ischemic injury.