Burak Yulug

Melatonin reduces disseminate neuronal death after mild focal ischemia in mice via inhibition of caspase‐3 and is suitable as an add‐on treatment to tissue‐plasminogen activator

Abstract:  The effects of i.p. melatonin (4 + 4 mg/kg, after induction of ischemia and at reperfusion onset) administered either alone or in combination with the thrombolytic tissue‐plasminogen activator (t‐PA, 10 mg/kg), on cerebral laser Doppler flow (LDF) and ischemic injury were studied after 30 min of middle cerebral artery (MCA) thread occlusion in male C57BL/6 mice. Thread occlusions resulted in reproducible focal ischemias, followed by hyperperfusion reactions immediately after thread withdrawal, as revealed by LDF measurements. Compared with animals receiving normal saline (peak LDF after reperfusion: 172.0 ± 24.2%), postischemic LDF was significantly attenuated in animals treated with melatonin (105.1 ± 6.7%, P < 0.05). Delivery of t‐PA (132.8 ± 22.3%) or t‐PA plus melatonin (164.7 ± 36.7%), on the contrary, did not influence postischemic LDF recordings. Twenty‐four hours after reperfusion, melatonin treated mice had significantly increased neuronal survival and decreased disseminate cell injury in the ischemia‐vulnerable striatum, as investigated by cresyl violet and terminal transferase biotinylated‐dUTP nick end labeling stainings. The protective effects were associated with inhibition of caspase‐3 activity. Melatonin administration also increased neuronal survival after 30 min MCA occlusion in animals treated with t‐PA, although t‐PA itself already decreased the degree of injury in a significant manner. Our data demonstrate that melatonin reduces disseminated neuronal injury in the striatum after mild focal ischemia. Brain protection is independent of hemodynamic changes and involves inhibition of caspase‐3.

Rifampicin attenuates brain damage in focal ischemia.

Rifampicin is an antibacterial agent that is widely used in tuberculosis and leprosy therapy. Interestingly, some experimental studies indicate that rifampicin acts as a hydroxyl radical scavenger and a glucocorticoid receptor activator. In this study, the neuroprotective effect of rifampicin was evaluated after transient and permanent focal cerebral ischemia. Anaesthetized male C57BL/6j mice were submitted to permanent or transient thread occlusion of the middle cerebral artery (MCA). Reperfusion in transient ischemia was initiated 30 min later by thread retraction. Rifampicin or vehicle were applied intraperitoneally before permanent or immediately after 30 min of transient ischemia. Later, 24 h after permanent or transient ischemia, animals were re-anesthetized and decapitated. Brain injury was evaluated by triphenyltetrazolium chloride staining (TTC), terminal transferase biotinylated-dUTP nick end labeling (TUNEL) and cresyl violet staining. A 20-mg/kg sample of rifampicin showed a significant neuroprotection after cerebral ischemia. The number of TUNEL-positive cells in the striatum, where disseminated tissue injury was observed, was also reduced by application of rifampicin as compared with vehicle-treated animals. The present report shows that administration of rifampicin efficiently reduces brain injury after permanent and transient focal cerebral ischemia in mice.

Risperidone attenuates brain damage after focal cerebral ischemia in vivo

Since their introduction, atypical neuroleptic agents have been discovered to have some beneficial effects beyond their effectiveness as neuroleptic drugs. Among these initially unexpected effects are their potential effects as mood stabilizers in bipolar disorder and their efficacy in improving long-term outcome in schizophrenia. These effects recently raised the question whether these drugs may also have some neuroprotective effect in the brain. To examine this matter, in this study we evaluated the neuroprotective effect of risperidone after permanent focal cerebral ischemia. Anaesthetized male C57BL/6j mice were submitted to permanent thread occlusion of the middle cerebral artery (MCA). Risperidone (0.1, 1 or 10 mg/kg) or vehicle was applied intraperitoneally just after permanent ischemia. Twenty-four hours after permanent ischemia, brain injury was evaluated by triphenyltetrazolium chloride staining (TTC). Risperidone (0.1, 1 and 10 mg/kg) showed significant neuroprotection after permanent focal cerebral ischemia.

Effects of normobaric oxygen and melatonin on reperfusion injury: role of cerebral microcirculation

In order to protect the brain before an irreversible injury occurs, penumbral oxygenation is the primary goal of current acute ischemic stroke treatment. However, hyperoxia treatment remains controversial due to the risk of free radical generation and vasoconstriction. Melatonin is a highly potent free radical scavenger that protects against ischemic stroke. Considering its anti-oxidant activity, we hypothesized that melatonin may augment the survival-promoting action of normobaric oxygen (NBO) and prevent brain infarction. Herein, we exposed mice to 30 or 90 min of intraluminal middle cerebral artery occlusion (MCAo) and evaluated the effects of NBO (70% or 100% over 90 min), administered either alone or in combination with melatonin (4 mg/kg, i.p.), on disseminate neuronal injury, neurological deficits, infarct volume, blood-brain barrier (BBB) permeability, cerebral blood flow (CBF) and cell signaling. Both NBO and particularly melatonin alone reduced neuronal injury, neurological deficits, infarct volume and BBB permeability, and increased post-ischemic CBF, evaluated by laser speckle imaging (LSI). They also improved CBF significantly in the ischemic- core and penumbra, which was associated with reduced IgG extravasation, DNA fragmentation, infarct volume, brain swelling and neurological scores. Levels of phosphorylated Akt, anti-apoptotic Bcl-xL, pro-apoptotic Bax and endothelial nitric oxide synthase (NOS) were re-regulated after combined oxygen and melatonin delivery, whereas neuronal and inducible NOS, which were increased by oxygen treatment, were not influenced by melatonin. Our present data suggest that melatonin and NBO are promising approaches for the treatment of acute-ischemic stroke, which encourage proof-of-concept studies in human stroke patients.

RIFAMPICIN: An antibiotic with brain protective function

Besides its well known antibiotic activity rifampicin exerts multiple brain protective functions in acute cerebral ischemia and chronic neurodegeneration. The present mini-review gives an update of the unique activity of rifampicin in different diseases including Parkinsons disease, meningitis, stroke, Alzheimers disease and optic nerve injury.

Particular phosphorylation of PI3K/Akt on Thr308 via PDK-1 and PTEN mediates melatonin's neuroprotective activity after focal cerebral ischemia in mice

Apart from its potent antioxidant property, recent studies have revealed that melatonin promotes PI3K/Akt phosphorylation following focal cerebral ischemia (FCI) in mice. However, it is not clear (i) whether increased PI3K/Akt phosphorylation is a concomitant event or it directly contributes to melatonins neuroprotective effect, and (ii) how melatonin regulates PI3K/Akt signaling pathway after FCI. In this study, we showed that Akt was intensively phosphorylated at the Thr308 activation loop as compared with Ser473 by melatonin after FCI. Melatonin treatment reduced infarct volume, which was reversed by PI3K/Akt inhibition. However, PI3K/Akt inhibition did not inhibit melatonins positive effect on brain swelling and IgG extravasation. Additionally, phosphorylation of mTOR, PTEN, AMPKα, PDK1 and RSK1 were increased, while phosphorylation of 4E-BP1, GSK-3α/β, S6 ribosomal protein were decreased in melatonin treated animals. In addition, melatonin decreased apoptosis through reduced p53 phosphorylation by the PI3K/Akt pathway. In conclusion, we demonstrated the activation profiles of PI3K/Akt signaling pathway components in the pathophysiological aspect of ischemic stroke and melatonins neuroprotective activity. Our data suggest that Akt phosphorylation, preferably at the Thr308 site of the activation loop via PDK1 and PTEN, mediates melatonins neuroprotective activity and increased Akt phosphorylation leads to reduced apoptosis.

The Neuroprotective Effect of Olanzapine

Case Report Mr. W is a 50-year-old Caucasian male who underwent a left frontotemporal craniotomy for a cerebral aneurysm originating from the P2 segment of the left posterior cerebral artery. Several months after the surgery, he developed major depression for which he was treated with escitalopram. As there was minimal improvement of his symptoms he was referred to the Johns Hopkins Brain Injury Clinic. His family history was significant for bipolar disorder in one brother and major depression in another brother. Prior to the brain surgery, Mr. W had never been diagnosed with psychiatric or medical problems. On cognitive testing, he scored 25 on the Mini-Mental State Examination, losing three points on recall, one on repetition of a sentence, and one on copying the intersecting pentagons. We increased the dose of escitalopram from 10 to 20 mg and recommended weekly psychotherapy. His mood stabilized temporarily, but he returned almost 2 years later with several days’ history of elated mood, increased energy, poor sleep, and racing thoughts. On the Young Mania Rating Scale, he scored 16. The dose of escitalopram was reduced to 10 mg and he was started on divalproex sodium, 500 mg/day, which was quickly increased to 1000 mg/day. Once again on this regimen, his mood symptoms stabilized. He remained euthymic for the next several months. During a follow-up evaluation almost a year later, he was started on donepezil, 5 mg, for inattention and short-term memory problems. Three weeks later, he presented with hypomanic symptoms which had begun after the initiation of donepezil. He scored 15 on the Young Mania Rating Scale. Donepezil was stopped with complete resolution of hypomanic symptoms and decreased his score on the Young Mania Rating Scale to 2.

Targeting different pathophysiological events after traumatic brain injury in mice: Role of melatonin and memantine

The tissue damage that emerges during traumatic brain injury (TBI) is a consequence of a variety of pathophysiological events, including free radical generation and over-activation of N-methyl-d-aspartate-type glutamate receptors (NMDAR). Considering the complex pathophysiology of TBI, we hypothesized that combination of neuroprotective compounds, targeting different events which appear during injury, may be a more promising approach for patients. In this context, both NMDAR antagonist memantine and free radical scavenger melatonin are safe in humans and promising agents for the treatment of TBI. Herein, we examined the effects of melatonin administered alone or in combination with memantine on the activation of signaling pathways, injury development and DNA fragmentation. Both compounds reduced brain injury moderately and the density of DNA fragmentation significantly. Notably, melatonin/memantine combination decreased brain injury and DNA fragmentation significantly, which was associated with reduced p38 and ERK-1/2 phosphorylation. As compared with melatonin and memantine groups, SAPK/JNK-1/2 phosphorylation was also reduced in melatonin/memantine combined animals. In addition, melatonin, memantine and their combination decreased iNOS activity significantly. Here, we provide evidence that melatonin/memantine combination protects brain from traumatic injury, which was associated with decreased DNA fragmentation, p38 phosphorylation and iNOS activity.

Neuroprotective treatment strategies for poststroke mood disorders: A minireview on atypical neuroleptic drugs and selective serotonin re-uptake inhibitors.

In our minireview we summarize the neuroprotective effect of atypical antipsychotic and selective serotonin re-uptake inhibitors after cerebral ischemia. In regard of increasing rate of poststroke mood disorders and current evidences indicating to an increased rate of cerebrovascular accidents after neuroleptic usage by the elderly population we also reviewed the clinical relevance of the neuroprotective and mood stabilizing effect of atypical antipsychotic agents in the light of basic pathophysiology of stroke.

Does sleep disturbance affect the amyloid clearance mechanisms in alzheimer's disease?

Sleep is an important factor that plays a key role in Alzheimers disease pathogenesis. However, it is still unclear whether poor‐quality sleep may overlap with sleep disturbances in the underlying dysfunctional mechanisms of amyloid beta (Aβ) clearance metabolism. Here, we aimed to evaluate the current evidence on the role of sleep deprivation in Aβ clearance metabolism. To that end, we discuss possible mechanisms underlying the bidirectional interaction between the sleep deprivation and Aβ clearance pathways.