Thavarak Ouk

PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases

PPARs (peroxisome-proliferator-activated receptors) are ligand-activated transcriptional factor receptors belonging to the so-called nuclear receptor family. The three isoforms of PPAR (alpha, beta/delta and gamma) are involved in regulation of lipid or glucose metabolism. Beyond metabolic effects, PPARalpha and PPARgamma activation also induces anti-inflammatory and antioxidant effects in different organs. These pleiotropic effects explain why PPARalpha or PPARgamma activation has been tested as a neuroprotective agent in cerebral ischaemia. Fibrates and other non-fibrate PPARalpha activators as well as thiazolidinediones and other non-thiazolidinedione PPARgamma agonists have been demonstrated to induce both preventive and acute neuroprotection. This neuroprotective effect involves both cerebral and vascular mechanisms. PPAR activation induces a decrease in neuronal death by prevention of oxidative or inflammatory mechanisms implicated in cerebral injury. PPARalpha activation induces also a vascular protection as demonstrated by prevention of post-ischaemic endothelial dysfunction. These vascular effects result from a decrease in oxidative stress and prevention of adhesion proteins, such as vascular cell adhesion molecule 1 or intercellular cell-adhesion molecule 1. Moreover, PPAR activation might be able to induce neurorepair and endothelium regeneration. Beyond neuroprotection in cerebral ischaemia, PPARs are also pertinent pharmacological targets to induce neuroprotection in chronic neurodegenerative diseases.

Rivastigmine in apathetic but dementia and depression-free patients with Parkinson's disease: a double-blind, placebo-controlled, randomised clinical trial

Background Even with optimal dopaminergic treatments, many patients with Parkinsons disease (PD) are frequently incapacitated by apathy prior to the development of dementia. We sought to establish whether rivastigmines ability to inhibit acetyl- and butyrylcholinesterases could relieve the symptoms of apathy in dementia-free, non-depressed patients with advanced PD. Methods We performed a multicentre, parallel, double-blind, placebo-controlled, randomised clinical trial (Protocol ID: 2008-002578-36; clinicaltrials.gov reference: NCT00767091) in patients with PD with moderate to severe apathy (despite optimised dopaminergic treatment) and without dementia. Patients from five French university hospitals were randomly assigned 1:1 to rivastigmine (transdermal patch of 9.5 mg/day) or placebo for 6 months. The primary efficacy criterion was the change over time in the Lille Apathy Rating Scale (LARS) score. Finding 101 consecutive patients were screened, 31 were eligible and 16 and 14 participants were randomised into the rivastigmine and placebo groups, respectively. Compared with placebo, rivastigmine improved the LARS score (from −11.5 (−15/−7) at baseline to −20 (−25/−12) after treatment; F(1, 25)=5.2; p=0.031; adjusted size effect: −0.9). Rivastigmine also improved the caregiver burden and instrumental activities of daily living but failed to improve quality of life. No severe adverse events occurred in the rivastigmine group. Interpretation Rivastigmine may represent a new therapeutic option for moderate to severe apathy in advanced PD patients with optimised dopaminergic treatment and without depression dementia. These findings require confirmation in a larger clinical trial. Our results also confirmed that the presence of apathy can herald a pre-dementia state in PD. Registration Clinicaltrials.gov reference: NCT00767091.

Withdrawal of fenofibrate treatment partially abrogates preventive neuroprotection in stroke via loss of vascular protection.

To explore the mechanisms of action of preventive neuroprotection induced by PPAR-alpha activation, we have evaluated the neuronal, vascular effects of preventive treatment with fenofibrate up until the induction of experimental brain ischaemia and fenofibrate treatment withdrawn 3days before ischaemia induction. Fenofibrate (200mg/kg/day) was administered in rats for 14days or withdrawn 3days before induction of cerebral ischaemia. Animals underwent a 1-hour middle cerebral artery occlusion (MCAo), followed by reperfusion for 24h. The MCAs vasoreactivity was analyzed and brain sections were used to assess infarct size, inflammatory and oxidative stress markers. Fenofibrate administration significantly decreases the cerebral infarct volume. This effect was associated with partial prevention of post-ischaemic endothelial dysfunction. However, withdrawal of the fenofibrate treatment 3days before the induction of ischaemia reduced the neuroprotection and was less beneficial in preventing endothelial dysfunction as well as superoxide anion production. In contrast, fenofibrate significantly reduced microglial activation and neutrophil infiltration into the ischaemic zone to a similar extent in both treatment modes. Our results show that the fenofibrate-induced cerebral protective effect may be related to both an acute effect and a preconditioning-like mechanism. The vascular protective effect appears rather to translate the acute effects of fenofibrate administration.

PPARs: a potential target for a disease-modifying strategy in stroke.

Stroke is one of the major causes of mortality and disability in adults in industrialized countries. Despite numerous preclinical studies and clinical trials in the field of cerebral ischemia, no pharmacological agent has been validated in the treatment of acute ischemic, except thrombolysis. Cerebral ischemia is not only a neuronal disease but it affects the entire neurovascular unit. The therapeutic strategy in stroke should be more global and combine preventive approaches, acute phase treatment and long-term care to improve recovery and prevent or treat affective and cognitive post-stroke consequences. There is an imperative need to develop disease-modifying drugs, which should be able to induce neuroprotection, to serve as adjuvants for thrombolysis by decreasing the hemorrhagic risk and to limit the long-term post-stroke consequences. This review presents the potential effects of Peroxisome Proliferator-Activated Receptors (PPARs) and of their agonists in stroke. We focus on each PPAR receptor and detail their implication in stroke. PPARs are nuclear receptors, acting as ligand-dependent transcription factors. They are expressed in the neurovascular unit that suggests that PPARs could play a role in stroke. Indeed, it has been shown that they are able to interfere with pathways implicated in the pathophysiology of stroke. They could be an answer to this disease-modifying drug concept, being able to act on the different phases of ischemia.

Early treatment with atorvastatin exerts parenchymal and vascular protective effects in experimental cerebral ischaemia.

From the clinical and experimental data available, statins appear to be interesting drug candidates for preventive neuroprotection in ischaemic stroke. However, their acute protective effect is, as yet, unconfirmed.

Lipid-lowering drugs prevent neurovascular and cognitive consequences of cardiopulmonary bypass

Inflammatory injury and hypoperfusion following cardiopulmonary bypass (CPB) are associated with potential brain injury in relationship between CPB, memory impairment, changes in cerebral vascular reactivity and both systemic and cerebral inflammatory reaction. The objective of this study was to assess the preventive effect of a pretreatment with simvastatin or fenofibrate on neurovascular and cognitive consequences of CPB. Male Sprague-Dawley rats were treated by control diet, simvastatin 10 mg/kg/day or fenofibrate 200 mg/kg/day for 14 days before CPB surgery and were sacrificed immediately after surgery or 24h later. Cognitive function, vascular reactivity, neuronal counts in CA1 and CA3 hippocampal regions, and inflammatory markers were assessed. CPB induced memory impairment and endothelial dysfunction 24h after surgery associated with neuronal loss. Neuronal loss was reduced by simvastatin or fenofibrate treatment in parallel to memory alteration prevention. Pretreatment by simvastatin and fenofibrate prevented CPB-induced endothelial dysfunction. CPB led to early and marked release of TNFα and overexpression of ICAM-1. Both inflammatory marker expression was decreased in the pretreated groups by lipid-lowering drugs. In a rat model of CPB, we demonstrated that simvastatin and fenofibrate protected against CPB-induced endothelial dysfunction, cerebral and systemic inflammation in parallel to memory impairment prevention.

PPAR-Alpha Agonist Used at the Acute Phase of Experimental Ischemic Stroke Reduces Occurrence of Thrombolysis-Induced Hemorrhage in Rats

The impact of fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR-α) agonist, on the risk of thrombolysis-induced hemorrhage during the acute phase of stroke in a rat model of stroke was studied. One-hour middle cerebral artery occlusion followed by thrombolysis with tissue plasminogen activator was made in rats receiving either fenofibrate or vehicle for 72 h after stroke. Evaluation of infarct, hemorrhage, middle cerebral artery vasoreactivity, and immunochemistry (CD11b for microglial activation, myeloperoxidase, and ICAM-1 for neutrophil infiltration) was performed. The PPAR-alpha agonist significantly reduced the risk of hemorrhage after thrombolysis in parallel with a decrease in the infarct volume and in the stroke-induced vascular endothelial dysfunction. These effects are concomitant with a reduction in microglial activation and neutrophil infiltration in infarct area. Our results strengthen the idea that using drugs such as fenofibrate, with pleiotropic properties due to PPAR-alpha agonism, may be of value to reduce thrombolysis-induced hemorrhage during acute stroke.

Proportion of single-chain recombinant tissue plasminogen activator and outcome after stroke

Objective: To determine whether the ratio single chain (sc)/(sc + 2 chain [tc]) recombinant tissue plasminogen activator (rtPA) influences outcomes in patients with cerebral ischemia. Methods: We prospectively included consecutive patients treated with IV rtPA for cerebral ischemia in 13 stroke centers and determined the sc/(sc + tc) ratio in the treatment administered to each patient. We evaluated the outcome with the modified Rankin Scale (mRS) at 3 months (prespecified analysis) and occurrence of epileptic seizures (post hoc analysis). We registered Outcome of Patients Treated by IV Rt-PA for Cerebral Ischaemia According to the Ratio Sc-tPA/Tc-tPA (OPHELIE) under ClinicalTrials.gov identifier no. NCT01614080. Results: We recruited 1,004 patients (515 men, median age 75 years, median onset-to-needle time 170 minutes, median NIH Stroke Scale score 10). We found no statistical association between sc/(sc + tc) ratios and handicap (mRS > 1), dependency (mRS > 2), or death at 3 months. Patients with symptomatic intracerebral hemorrhages had lower ratios (median 69% vs 72%, adjusted p = 0.003). The sc/(sc + tc) rtPA ratio did not differ between patients with and without seizures, but patients with early seizures were more likely to have received a sc/(sc + tc) rtPA ratio >80.5% (odds ratio 3.61; 95% confidence interval 1.26–10.34). Conclusions: The sc/(sc + tc) rtPA ratio does not influence outcomes in patients with cerebral ischemia. The capacity of rtPA to modulate NMDA receptor signaling might be associated with early seizures, but we observed this effect only in patients with a ratio of sc/(sc + tc) rtPA >80.5% in a post hoc analysis.

Time-induced progressive alteration of kir current in cerebral smooth muscle cells of stroke-prone spontaneously hypertensive rats.

We investigated the involvement of potassium inward rectifier current (Kir) impairment in smooth muscle cells of cerebral arteries under the condition of increased susceptibility of stroke, in spontaneously hypertensive stroke-prone (SHRsp) rats compared to spontaneously hypertensive (SHR) ones as well as to controls (WKY). Kir current was studied with whole-cell patch-clamp techniques on freshly isolated single smooth muscle cells (SMC) of middle cerebral artery (MCA) from SHRsp, SHR, and WKY male rats (are range 12–32 weeks). A significant and progressive Kir current density reduction was observed on SMC of SHRsp rats from the 22nd week of age on, as opposed to the Kir current density stability observed over the same time in the SMC of WKY and SHR rats. The Kir density alteration was correlated to the age of the SHRsp animals. These results suggest that in the cerebral vascular smooth muscle cells of SHRsp rats, there is a progressive Kir channel impairment, leading to a reduction of Kir current density. This impairment may underpin a lack of vasodilation of the MCA and be implicated in the stroke-proneness observed on SHRsp animals.

Neutrophils in tPA-induced hemorrhagic transformations: Main culprit, accomplice or innocent bystander?

ABSTRACT The risk of intracerebral hemorrhage still greatly limits the use of tPA in stroke patients. Research is ongoing in order to identify the pathophysiological mechanisms at play, detect predictive biomarkers and discover new pharmacological targets to develop preventive or curative treatments. Going through experimental and clinical studies, this review focuses on the role of neutrophils as key predictive biomarkers for thrombolysis‐induced hemorrhages and as pharmacological targets to limit their occurrence. To date, there are no established pharmacological modulators of neutrophils for ischemic stroke and its hemorrhagic complications. Several strategies are under evaluation, including lipid‐lowering drugs, free radical scavengers, or minocycline, as well as non‐pharmacological interventions such as physical exercise.