Mounzer Kassab

Asiatic acid, a pentacyclic triterpene from Centella asiatica, is neuroprotective in a mouse model of focal cerebral ischemia

Asiatic acid, a triterpenoid derivative from Centella asiatica, has shown biological effects such as antioxidant, antiinflammatory, and protection against glutamate‐ or β‐amyloid‐induced neurotoxicity. We investigated the neuroprotective effect of asiatic acid in a mouse model of permanent cerebral ischemia. Various doses of asiatic acid (30, 75, or 165 mg/kg) were administered orally at 1 hr pre‐ and 3, 10, and 20 hr postischemia, and infarct volume and behavioral deficits were evaluated at day 1 or 7 postischemia. IgG (blood–brain barrier integrity) and cytochrome c (apoptosis) immunostaining was carried out at 24 hr postischemia. The effect of asiatic acid on stress‐induced cytochrome c release was examined in isolated mitochondrial fractions. Furthermore, its effects on cell viability and mitochondrial membrane potential were studied in HT‐22 cells exposed to oxygen‐glucose deprivation. Asiatic acid significantly reduced the infarct volume by 60% at day 1 and by 26% at day 7 postischemia and improved neurological outcome at 24 hr postischemia. Our studies also showed that the neuroprotective properties of asiatic acid might be mediated in part through decreased blood–brain barrier permeability and reduction in mitochondrial injury. The present study suggests that asiatic acid may be useful in the treatment of cerebral ischemia.

The therapeutic potential of statins in neurological disorders.

Statins are currently among the most commonly prescribed agents for the prevention of cardiovascular disease. Statins reduce serum cholesterol levels by reversibly inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol biosynthesis, in the nanomolar range. Mounting evidence suggests that in addition to their vascular effects such as stabilization of atherosclerotic plaques and decreased carotid intimal-medial thickness, statins have additional properties such as endothelial protection via actions on the nitric oxide synthase system as well as antioxidant, anti-inflammatory and anti-platelet effects. These effects of statins might have potential therapeutic implications in various neurological disorders such as stroke, Alzheimers disease, Parkinsons disease, multiple sclerosis and primary brain tumors. In this review, the major protective mechanisms of statins and their applicability to the treatment of neurological disease are summarized. Although further experiments are required, currently available data would seem to indicate that clinical trials to determine the safety and efficacy of statins in a number of disorders are warranted.

Neuroprotective effect of cyanidin-3-O-glucoside anthocyanin in mice with focal cerebral ischemia

The present study sought to determine the neuroprotective effect of anthocyanin cyanidin-3-O-glucoside (CG), isolated and purified from tart cherries, against permanent middle cerebral artery occlusion (pMCAO) in mice and its potential mechanisms of neuroprotection. C57BL/6 mice subjected to pMCAO were treated with CG orally. Twenty-four hours after pMCAO, neurological scoring was used to evaluate functional outcome. The brains were then excised for measuring infarct volume and brain superoxide levels were determined. In a separate set of experiments, the influence of CG on cytochrome c (cyt c) and apoptosis-inducing factor (AIF) release from mitochondria under oxidative stress were assessed in isolated cortical neurons from adult mouse brains. Infarction volume was attenuated by 27% in mice pre-treated with 2mg/kg of CG compared to vehicle-treated mice. Delayed treatment with 2mg/kg of CG also showed 25% reduction in infarct size. Neurological functional outcome was significantly improved in mice pre- or post-treated with CG. Compared to vehicle treated mice CG treated mice had lower levels of brain superoxide. CG also blocked the release of AIF from mitochondria under oxidative stress, but did not inhibit the release of cyt c. Our data show that CG is neuroprotective against pMCAO in mice, and this beneficial effect may be mediated by attenuation of brain superoxide levels after ischemia. CG may also exert its neuroprotective effect by blocking AIF release in mitochondria.

Predictors of Occult Paroxysmal Atrial Fibrillation in Cryptogenic Strokes Detected by Long-Term Noninvasive Cardiac Monitoring

Background and Purpose. Paroxysmal Atrial fibrillation/Flutter (PAF) detection rates in cryptogenic strokes have been variable. We sought to determine the percentage of patients with cryptogenic stroke who had PAF on prolonged non-invasive cardiac monitoring. Methods and Results. Sixty-two consecutive patients with stroke and TIA in a single center with a mean age of 61 (+/− 14) years were analyzed. PAF was detected in 15 (24%) patients. Only one patient reported symptoms of shortness of breath during the episode of PAF while on monitoring, and 71 (97%) of these 73 episodes were asymptomatic. A regression analysis revealed that the presence of PVCs (ventricular premature beats) lasting more than 2 minutes (OR 6.3, 95% CI, 1.11–18.92; P = .042) and strokes (high signal on Diffusion Weighted Imaging) (OR 4.3, 95% CI, 5–36.3; P = .041) predicted PAF. Patients with multiple DWI signals were more likely than solitary signals to have PAF (OR 11.1, 95% CI, 2.5–48.5, P < .01). Conclusion. Occult PAF is common in cryptogenic strokes, and is often asymptomatic. Our data suggests that up to one in five patients with suspected cryptogenic strokes and TIAs have PAF, especially if they have PVCs and multiple high DWI signals on MRI.

Differential Neuroprotective Effects of Carnosine, Anserine, and N-Acetyl Carnosine against Permanent Focal Ischemia

Carnosine (β‐alanyl‐L‐histidine) has been shown to exhibit neuroprotection in rodent models of cerebral ischemia. In the present study, we further characterized the effects of carnosine treatment in a mouse model of permanent focal cerebral ischemia and compared them with its related peptides anserine and N‐acetylated carnosine. We also evaluated the efficacy of bestatin, a carnosinase inhibitor, in ameliorating ischemic brain damage. Permanent focal cerebral ischemia was induced by occlusion of the middle cerebral artery (pMCAO). Mice were subsequently randomly assigned to receive an intraperitoneal injection of vehicle (0.9% saline), carnosine, N‐acetyl carnosine, anserine, bestatin alone, or bestatin with carnosine. Infarct size was examined using 2,3,5‐triphenyltetrazolium chloride staining 1, 3, and 7 days following pMCAO, and neurological function was evaluated using an 18‐point‐based scale. Brain levels of carnosine were measured in treated mice using high‐performance liquid chromatography 1 day following pMCAO. We demonstrated that treatment with carnosine, but not its analogues, was able to significantly reduce infarct volume and improve neurological function compared with those in vehicle‐treated mice. These beneficial effects were maintained for 7 days post‐pMCAO. In contrast, compared with the vehicle‐treated group, bestatin‐treated mice displayed an increase in the severity of ischemic lesion, which was prevented by the addition of carnosine. These new data further characterize the neuroprotective effects of carnosine and suggest that carnosine may be an attractive candidate for testing as a stroke therapy.

Transcranial doppler: An introduction for primary care physicians

Transcranial Doppler (TCD) is a diagnostic tool that can be used at bedside to assess the cerebral vasculature noninvasively. It is inexpensive, safe, and reliable when compared with other techniques. It can be repeated multiple times and can be used for continuous monitoring if needed. Screening of children with sickle cell disease to assess and prevent ischemic strokes and monitoring for vasospasm after subarachnoid hemorrhage are well established, evidenced based utilizations of TCD. It is useful for the evaluation of occlusive intracranial vascular lesions with many emerging indications in the management of ischemic stroke. TCD with micro-bubble enhancement has comparable sensitivity to transesophageal echocardiogram in detecting right-to-left atrial cardiac shunts. TCD is underused as a clinical tool despite well established indications. The pressure to contain increasing medical cost will likely result in increased utilization of this test in future.

The role of optical coherence tomography in vascular medicine

Abstract Optical coherence tomography (OCT) is an emerging imaging modality that provides high-resolution, microstructural information on atherosclerotic plaques in biological systems. Intracoronary OCT can identify thin-cap fibroatheroma and other vulnerable plaques that may be responsible for acute coronary events. These characteristics make OCT helpful in guiding coronary management and interventions, including stent apposition and early identification of procedure-related complications. OCT is being assessed for its potential role in carotid plaque characterization and in the diagnosis of peripheral arterial atherosclerosis. Its current use in studying carotid and cerebral vasculature and in the diagnosis of peripheral arterial diseases is limited and ill defined, but it is finding increasing application in these areas. Its performance can be further improved by increasing the signal to noise ratio and by using dynamic focus tracking techniques. It can potentially be used to monitor the progression and regression of atherosclerosis in the coronary, cerebral and peripheral vasculature. New indications for its use in vascular medicine are emerging as its technology continues to improve over time.

Cardiac Dysfunction After Left Permanent Cerebral Focal Ischemia The Brain and Heart Connection

Background and Purpose— Stroke can lead to cerebrogenic cardiac arrhythmias. We sought to investigate the effect of ischemic stroke on cardiac function in a mouse model of permanent middle cerebral artery occlusion (pMCAO). Methods— Twenty-four hours after the induction of focal ischemia, cardiac function was measured in mice by endovascular catheterization of the heart. Immediately after hemodynamic measurements, mice were euthanized and brains were excised and sectioned to measure infarct volume and the severity of insular cortex injury. Myocardial damage was evaluated by hematoxylin-eosin staining. Serum and heart levels of norepinephrine (NE) were also determined. Results— Cardiac dysfunction occurred in 9 out of 14 mice that underwent left pMCAO. In these 9 mice, the severity of left insular cortex lesion was greater than the mice with normal heart function. The serum and heart levels of NE were significantly higher in left pMCAO mice with heart dysfunction. Liner regression analysis indicates significant inverse correlation between the severity of left insular cortex damage and heart dysfunction. Mice that underwent right pMCAO did not exhibit cardiac dysfunction. Conclusions— This study shows that left focal cerebral ischemia can produce cardiac dysfunction, which is associated with the extent of left insular cortex damage. Furthermore, mice exhibiting cardiac dysfunction had elevated levels of NE in the serum and heart.

Levetiracetam for managing neurologic and psychiatric disorders

PURPOSE The role of levetiracetam in different epileptic, nonepileptic, neurologic, and psychiatric disorders is discussed. SUMMARY Levetiracetam, an antiepileptic drug (AED), was first approved as an adjunctive therapy for the treatment of partial epilepsy in adults. It is currently being used in the treatment of multiple seizure disorders, including generalized tonic-clonic; absence; myoclonic, especially juvenile myoclonic; Lennox-Gastaut syndrome; and refractory epilepsy in children and adults. Data are emerging on possible uses of levetiracetam outside the realm of epilepsy because of its unique mechanisms of action. There is preliminary evidence about the efficacy of levetiracetam in the treatment of different psychiatric disorders, including anxiety, panic, stress, mood and bipolar, autism, and Tourettes syndrome. The most serious adverse effects associated with levetiracetam use are behavioral in nature and might be more common in patients with a history of psychiatric and neurobehavioral problems. CONCLUSION Levetiracetam is an effective AED with potential benefits in other neurologic and psychiatric disorders. The benefit-risk ratio in an individual patient with a specific condition should be used to determine its optimal use. Levetiracetams use in nonepileptic conditions is not recommended until more data become available from larger trials.

Role of sildenafil in neurological disorders.

Sildenafil, a phosphodiesterase-5 inhibitor commonly used for erectile dysfunction, may also have a beneficial therapeutic effect in the treatment of stroke, subarachnoid hemorrhage, dementia, learning, and neurodegenerative disorders by enhancing angiogenesis and neurogenesis. It also favorably influences the nitric oxide-cyclic guanosine monophosphate pathways, which are involved in the pathogenesis of a number of neurological diseases. Its potential therapeutic role in the treatment of the neurological disorders mentioned above is still under preclinical investigation. Sildenafil is currently being used to treat erectile dysfunction in patients with multiple sclerosis, Parkinson disease, multisystem atrophy, and spinal cord injury by improving their neurologically related erectile dysfunction. Conversely, it has been implicated in a number of neurological problems, such as intracerebral hemorrhage, migraine, seizure, transient global amnesia, nonarteritic anterior ischemic optic neuropathy, macular degeneration, branch retinal artery occlusion, and ocular muscle palsies. Thus, preclinical and very limited clinical data suggest that sildenafil may have therapeutic potential in selected neurological disorders. However, numerous reports are available regarding neurological adverse events ascribed to the drug. Although sildenafil shows some promise as a therapeutic agent in selected neurological disorders, well-designed clinical trials are needed before the agent can be recommended for use in any neurological disorder.