Comparative Efficacy of Neuroprotective Agents for Improving Neurological Function and Prognosis in Acute Ischemic Stroke: A Network Meta-Analysis

 First of all, stop using the term, neuroprotection! Neuronal cascade of death is the correct term! It gives absolutely NO SENSE OF URGENCY! If you tell your patients, you know nothing about stopping  the 5 causes of the neuronal cascade of death in the first week thus letting die hundreds of millions to billions of neurons.  They might just get angry with your incompetence!

Send me hate mail on this: oc1dean@gmail.com. I'll print your complete statement with your name and my response in my blog. Or are you afraid to engage with my stroke-addled mind? I would like to know why you aren't solving stroke to 100% recovery, because this doesn't solve stroke recovery at all!

You'll have to ask your competent? doctor why the hell edaravone is approved in Japan since 2001 but not the US.

Has your stroke hospital done anything with any of these in the last decade? OR ARE THEY COMPLETELY FUCKING INCOMPENT AT EVERYTHING IN STROKE? 

 You can easily see how much research is out there to be implemented and your hospital is totally incompetent if not done. 

• Cerebrolysin (12 posts to June 2014)
• citicoline (15 posts to October 2011)

• minocycline (17 posts to May 2012)

• dl-NBP (1 post to April 2017)
• 
  
• NA-1 (5 posts to October 2012) 

• edaravone (12 posts to November 2011)

• Role of vinpocetine in ischemic stroke and poststroke outcomes: A critical review 2020

• Anti-inflammatory effects of vinpocetine in atherosclerosis and ischemic stroke: a review of the literature 2014

• A systematic review of vinpocetine therapy in acute ischaemic stroke 1999

• Vinpocetine inhibits NF-κB-dependent inflammation in acute ischemic stroke patients 2018

The latest here:

Comparative Efficacy of Neuroprotective Agents for Improving Neurological Function and Prognosis in Acute Ischemic Stroke: A Network Meta-Analysis

Yuchen Wang ^1,2 Mengqi Li ^1,2 Yuye Jiang ^1,2 Qiuhong JI ^1*

• ¹ Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
• ² School of Medicine, Nantong University, Nantong, Jiangsu Province, China

The final, formatted version of the article will be published soon.

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cause of combined disability and mortality globally. While reperfusion therapies play a critical role in the management of acute ischemic stroke (AIS), their applicability is limited, leaving many patients with significant neurological deficits and poor prognoses.Neuroprotective agents have garnered attention for their potential as adjunct therapies; however, their relative efficacy remains unclear. This study utilized a network metaanalysis (NMA) to systematically compare the efficacy of neuroprotective agents in improving neurological function and prognosis in stroke patients. Methods: This study adhered to PRISMA guidelines and the Cochrane Handbook for systematic reviews. Randomized controlled trials (RCTs) were identified through comprehensive searches of the PubMed, Embase, and Cochrane Library databases. Two independent reviewers conducted the selection process, data extraction, and quality assessment. Outcomes included 90-day modified Rankin Scale(90d-mRS)、change of National Institutes of Health Stroke Scale score from baseline to 90-day/14-day/7-day (90day/14d/7d-NIHSS) and 90-day/14-day Barthel Index (90d/14d-BI).Data analyses were performed using RevMan 5.4 and Stata 14.0. Results: A total of 42 RCTs involving 12,210 participants were included in this analysis. The interventions assessed included Cerebrolysin, Citicoline, Edaravone, Edaravone Dextranol, HUK, Minocycline, NA-1, NBP, Vinpocetine, and Control. The NMA results demonstrated that NBP ranked highest for the 90d-mRS, 90d-NIHSS, 14d-NIHSS, and 14d-BI outcomes. Edaravone was found to be the most effective intervention for the 7d-NIHSS and 90d-BI outcomes.The findings of this study indicate that different neuroprotective agents exhibit distinct advantages at specific stages of recovery. NBP showed outstanding performance in improving 90d-mRS and 90d-NIHSS, underscoring its potential in long-term rehabilitation. Edaravone demonstrated significant superiority in 7d-NIHSS scores, highlighting its role in early neuroprotection. These results provide valuable insights for individualized clinical treatment. To further validate the efficacy and safety of neuroprotective agents, future studies should involve larger sample sizes and conduct multicenter, large-scale randomized controlled trials.

Keywords: Neuroprotective Agents, Network meta-analysis, n-Butylphthalide, Edaravone, Neurological function, stroke rehabilitation

Received: 19 Nov 2024; Accepted: 13 Dec 2024.

Copyright: © 2024 Wang, Li, Jiang and JI. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.   

Vinpocetine Protects Against Cerebral Ischemia-Reperfusion Injury by Targeting Astrocytic Connexin43 via the PI3K/AKT Signaling Pathway

What is the EXACT METHOD your doctor is using to stop reperfusion injury? NOTHING? Then what research is your doctor working on to solve that problem?  You just might want to save those neurons that are dying during reperfusion. I'd suggest charging your doctor $1000 a dead neuron, that might concentrate the mind. Nothing else seems to get survivors closer to 100% recovery.

• reperfusion injury (26)

 

Vinpocetine Protects Against Cerebral Ischemia-Reperfusion Injury by Targeting Astrocytic Connexin43 via the PI3K/AKT Signaling Pathway

Mingming Zhao¹, Shuai Hou¹, Liangshu Feng¹, Pingping Shen¹, Di Nan¹, Yunhai Zhang^2,3, Famin Wang^2,3, Di Ma^1* and Jiachun Feng^1*

• ¹Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
• ²Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
• ³Jiangsu Key Laboratory of Medical Optics, Suzhou, China

Vinpocetine (Vinp) is known for its neuroprotective properties. However, the protective mechanism of Vinp against cerebral ischemia/reperfusion (I/R) injury should be further explored. This study was designed to investigate the neuroprotective effects of Vinp against oxygen-glucose deprivation/reoxygenation (OGD/R) injury in vitro and cerebral I/R injury in vivo and explore whether this mechanism would involve enhancement of astrocytic connexin 43 (Cx43) expression via the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. In vitro, we detected astrocytic viability and extracellular nitric oxide by an assay kit, intracellular reactive oxygen species by a DCFH-DA probe, inflammation and apoptosis-related protein expression by immunofluorescence staining, and the astrocytic apoptosis rate by flow cytometry. In vivo, we measured the cerebral infarction volume, superoxide dismutase activity, malondialdehyde content, and the expression of inflammation and apoptosis-related proteins. The results indicated that Vinp ameliorated the detrimental outcome of I/R injury. Vinp attenuated astrocytic injury induced by OGD/R and reduced cerebral infarction volume and cerebral edema in rats with cerebral I/R injury. Moreover, Vinp reduced oxidative stress, inflammation, and apoptosis induced by cerebral I/R injury in brain tissues. Meanwhile, Vinp increased p-Cx43 and p-AKT expression, and the p-Cx43/Cx43 and p-AKT/AKT ratio, which was decreased by cerebral I/R injury. Coadministration of PI3K inhibitors LY294002 and BKM120 blunted the effects of Vinp. This study suggests that Vinp protects against cerebral I/R injury via Cx43 phosphorylation by activating the PI3K/AKT pathway.

Introduction

Ischemic stroke has high morbidity and mortality and seriously affects patient quality of life (Ribeiro et al., 2015). Timely recovery of blood and oxygen supply to the ischemic brain tissue is essential for ischemic penumbra survival. Thrombolytic therapy is the best treatment option for ischemic stroke (Sheth et al., 2015). However, reperfusion aggravates the damage and provokes dysfunction through a cascade of events such as calcium overload, excitotoxicity, oxidative stress, inflammatory responses, and apoptosis, which are collectively termed “ischemia-reperfusion injury” (I/R injury) (Dirnagl et al., 1999). Therefore, effectively blocking the cascade of cerebral I/R injury and exploring effective drugs for the treatment of ischemic stroke are very important.

Astrocytes are abundant in the central nervous system, and they play essential roles in maintaining brain function under physiologic conditions and in influencing neuronal survival under pathologic conditions, such as cerebral I/R injury and other brain insults (Garman, 2011; Falkowska et al., 2015; Verkhratsky et al., 2017). During ischemic stroke, astrocytes may be activated and produce and release reactive oxygen species (ROS), pro-inflammatory cytokines, and other factors that may negatively influence the survival of neurons in the penumbra (Swanson et al., 2004). Thus, preventing astrocytic inflammatory and apoptotic effects may be a promising strategy for neuroprotection in ischemic stroke (Cekanaviciute and Buckwalter, 2016; Choudhury and Ding, 2016; Liu and Chopp, 2016).

The PI3K/AKT signaling pathway regulates a wide range of cellular functions, including cellular differentiation, proliferation, inflammation, and apoptosis (Cantley, 2002). Studies have shown that phosphorylation of AKT (Ser473) reduces neuronal apoptosis caused by cerebral I/R injury (Fukunaga and Kawano, 2003; Zhao et al., 2006), and LY294002-mediated inhibition of the PI3K/AKT pathway blocked the cardioprotective effect of atorvastatin against I/R injury in cardiocytes by downregulating Connexin 43 (Cx43) (Bian et al., 2015). Moreover, activated AKT can phosphorylate the C-terminal Ser373 residue of Cx43 (Solan and Lampe, 2014). Since Cx43 is the most commonly expressed gap junction protein in astrocytes (Orellana et al., 2011), and increased Cx43 expression can reduce neuronal damage after cerebral I/R (Nakase et al., 2003), we speculate that Cx43 is involved in the PI3K/AKT pathway’s protective effects against cerebral I/R injury.

Vinpocetine (Vinp) is a semi-synthetic alkaloid derivative isolated from the leaves of Phyllostachys pubescens. Its anti-inflammatory and anti-platelet aggregation effects on improving cerebral blood flow, brain metabolism, and cognition have been confirmed by various studies (Zhang et al., 2018; Zhang et al., 2018). Vinp has been widely used in the treatment of stroke, cerebral arteriosclerosis, and chronic cerebral insufficiency, and it exhibits unique advantages in the treatment of dementia and epilepsy. A previous study showed that Vinp similarly decreased the inflammatory response by inhibiting NF-κB and TNF-α expression after cerebral I/R injury (Wang et al., 2014); however, its specific mechanism remains unknown. Cerebral I/R injury can activate both astrocytes and microglia, which may produce inflammatory cytokines and other toxic mediators (Kim et al., 2016; Duris et al., 2018). Microglial TLR4/MyD88/NF-κB has been shown to be one of the mechanisms by which Vinp protects against cerebral I/R injury (Wu et al., 2017). However, so far, no study has focused on whether Vinp’s protective effects against cerebral I/R injury is related to astrocytes. Hence, we hypothesized that Vinp may affect astrocytic Cx43 via the PI3K/AKT pathway and thereby provide neuroprotection.

In this study, we explored the neuroprotective roles of vinpocetine against oxygen-glucose deprivation/reoxygenation (OGD/R) injury in vitro and cerebral I/R injury in vivo and explore whether this mechanism would involve enhancement of astrocytic connexin 43 (Cx43) expression via the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway.

21 Proven Ways to Increase Brain Blood Flow

I'm sure your doctor intimately knows of all of these and has stroke protocols for you immediately after your stroke. Assuming that your doctor thinks that increased blood flow to the brain is useful in stroke recovery. Don't do these on your own, way too dangerous.

21 Proven Ways to Increase Brain Blood Flow

1. Exercise 

2. Cold Exposure

3. Sunlight

4. Ginkgo Biloba

5. Low-Level Laser Therapy (LLLT)

6. Vinpocetine

7. Meditation

8. Resveratrol

9. Dark Chocolate 

10. Omega-3 Fatty Acids 

11. Acupuncture

12. Chewing Gum

13. Acetyl-L-Carnitine (ALCAR) 

14. Nitrates

15. Drink Less Coffee (Or Take Theanine)

16. Piracetam 

17. Ketogenic Dieting

18. Citicoline 

19. Blueberry Juice

20. Pyrroloquinoline Quinone (PQQ) 

21. Intranasal Insulin 

Details at link, even research. 

Anti-Inflammatory Effects of Vinpocetine in Atherosclerosis and Ischemic Stroke: A Review of the Literature

I'm sure no followup has occurred with NO stroke leadership.

Pros on using this:

Vinpocetine increases cerebral blood flow and oxygenation in stroke patients: a near infrared spectroscopy and transcranial Doppler study

 

Cons on using this:

 

Vinpocetine, for instance, has been observed to disrupt myelin repair, which could be especially problematic for MS patients.

 

Anti-Inflammatory Effects of Vinpocetine in Atherosclerosis and Ischemic Stroke: A Review of the Literature

Linjie Zhang and Li Yang *

Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, 154, Anshan Road, Heping District, Tianjin 300052, China

*

Author to whom correspondence should be addressed; Tel.: +86-22-6081-4536; Fax: +86-22-6081-7471.

Academic Editor: Derek J. McPhee

Received: 24 October 2014 / Accepted: 19 December 2014 / Published: 26 December 2014

Abstract

: Immune responses play an important role in the pathophysiology of atherosclerosis and ischemic stroke. Atherosclerosis is a common condition that increases the risk of stroke. Hyperlipidemia damages endothelial cells, thus initiating chemokine pathways and the release of inflammatory cytokines—this represents the first step in the inflammatory response to atherosclerosis. Blocking blood flow in the brain leads to ischemic stroke, and deprives neurons of oxygen and energy. Damaged neurons release danger-associated molecular patterns, which promote the activation of innate immune cells and the release of inflammatory cytokines. The nuclear factor κ-light-chain-enhancer of activated B cells κB (NF-κB) pathway plays a key role in the pathogenesis of atherosclerosis and ischemic stroke. Vinpocetine is believed to be a potent anti-inflammatory agent and has been used to treat cerebrovascular disorders. Vinpocetine improves neuronal plasticity and reduces the release of inflammatory cytokines and chemokines from endothelial cells, vascular smooth muscle cells, macrophages, and microglia, by inhibiting the inhibitor of the NF-κB pathway. This review clarifies the anti-inflammatory role of vinpocetine in atherosclerosis and ischemic stroke.

Russian Drugs Pass as Supplements in U.S. - vinpocetine and picamilon

Be careful out there.
http://www.medpagetoday.com/clinical-context/MultipleSclerosis/53840?xid=nl_mpt_DHE_2015-10-02&eun=g424561d0r
Two pharmaceutical-grade drugs are being marketed as brain-boosting botanical supplements, researchers found.
Both vinpocetine and picamilon are prescribed as cerebrovascular drugs in several other countries, but are sold as nutritional supplements in the U.S. and marketed to improve focus and memory. Neither is a simple botanical extract: vinpocetine is the product of heavy refinement of the alkaloid vincamine (found in the lesser periwinkle Vinca minor), while picamilon has no known natural source and is only produced synthetically.
There's been increasing interest in nootropics -- substances that boost cognitive function -- for healthy patients to prevent disease, as well as for patients with neurological or muscle diseases, including Alzheimer's, dementia, and multiple sclerosis (MS), but in some instances these compounds may cause more harm than good.
Vinpocetine, for instance, has been observed to disrupt myelin repair, which could be especially problematic for MS patients.
In an analysis of the brands of these supplements sold at GNC and the Vitamin Shoppe, many delivered the same daily doses as when the drug is prescribed pharmacologically, Pieter Cohen, MD, of Harvard Medical School and the Cambridge Health Alliance, and colleagues reported in Drug Testing and Analysis.
"The FDA has permitted an unapproved new drug with unproven efficacy and known adverse effects to be sold directly to consumers," Cohen wrote in an wrote in an accompanying commentary in Mayo Clinic Proceedings about vinpocetine. "The FDA should not permit unapproved drugs, even semisynthetic derivatives of natural compounds, to be sold as dietary supplements."
Vinpocetine is prescribed in Russia, China, Germany, and other countries for acute stroke and cognitive impairment, but it has never been approved by the FDA as a prescription drug.

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Data on its neuroprotective effects are conflicting, while its known side effects include flushing, headaches, and decreased blood pressure.
In 1997, a manufacturer submitted a new dietary ingredient notification to FDA, and since then it has been permitted as a supplement.
Cohen said the agency "may have assumed that vinpocetine was a botanical extract, but it is not." It can be synthesized from vincamine, which is found in the leaves of the lesser periwinkle, but it is the result of heavy processing and has never been identified by itself in any plant.
Nor is picamilion found in any known plant. It is fully synthetic and was first developed by Russian investigators to increase CNS levels of GABA for treating anxiety and seizures. It's currently used in Russia for various neurological conditions.
Unlike vinpocetine, it has never been submitted to the FDA, Cohen said.
For their study, Cohen and colleagues analyzed 23 brands of vinpocetine and 31 brands of picamilon supplements to determine the accuracy of their labels. They used the ultra-high performance liquid chromatography photodiode-array method to quantify these ingredients.
Only 26% of the vinpocetine brands provided consumers with accurate information about the dose of the ingredient in their product, Cohen said.
They found that 17 of the 23 vinpocetine brands contained quantities ranging from 0.3 mg to 32 mg per recommended daily serving -- with many of these falling in the pharmaceutical dose range of the drug, which is 5 mg to 40 mg. There was no vinpocetine in six samples.
They also compared two samples of Vinca minor and found the alkaloid vincamine, but there was no vinpocetine at all, they reported.
Of the 31 brands of picamilon supplements, 30 had quantities ranging from 2.7 mg to 721.5 mg per recommended daily serving. Prescription doses range from 50 mg to 200 mg.

"New drugs can bypass the rigorous drug approval process and can be sold directly to consumers without FDA approval," Cohen said.
The study was limited because the researchers only sampled one of each supplement, but Cohen said this kind of practice wouldn't be unusual in a system that doesn't require companies to report how much active ingredient is in the product or what its side effects might be.
He and his team concluded that the findings show that drugs prescribed as pharmaceuticals in other countries are being sold openly in dietary supplements in the U.S.
"It's pretty widely understood by both the FDA and industry that if you have to synthetically change a botanical compound, then it's a drug," Cohen told MedPage Today. "The Dietary Supplements Health and Education Act wasn't designed to regulate these kinds of products."
"Remarkably," he added, "the FDA has done nothing to intervene in the sale of these brain enhancing supplements containing unapproved drugs."

Vinpocetine increases cerebral blood flow and oxygenation in stroke patients: a near infrared spectroscopy and transcranial Doppler study

Only 13 years old so I wonder if this is in use anywhere. I had not heard of this before except it seems to help in middle ear infections. Acute or hyperacute?
http://www.sciencedirect.com/science/article/pii/S092982660200006X

• Péter Bönöczk^a,
• Gyula Panczel^b,
• Zoltán Nagy^{b, ,}

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doi:10.1016/S0929-8266(02)00006-X

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Abstract

Objective: To investigate the effect of vinpocetine on cerebral blood flow (CBF) in the compromised circulation of a stroke affected hemisphere using transcranial Doppler (TCD) and near infrared spectroscopy (NIRS) methods.  

Methods: 43 patients with ischemic stroke were randomized into vinpocetine (VP) and placebo group in a double blind, placebo-controlled study of the effect of a single-dose i.v. infusion of vinpocetine on cerebral blood perfusion and oxygenation. In the VP group 20 mg VP in 500 ml saline, in the placebo group 500 ml saline alone were administered. The concentrations of oxy-, reduced- and total hemoglobin were measured by NIRS frontolaterally on the side of lesion while the mean cerebral blood flow velocity (CBFV), the pulsatility index (PI) and Doppler spectral intensity (DSI) were monitored by TCD in the middle cerebral artery on the same side. Values were averaged for the first 5 min prior to the infusion and for the last 5 min of infusion and they were compared between groups.  

Results: The concentration of all three chromophores increased during infusion in the VP group (mean dHbT=1.03, CI₉₅=0.84, P=0.058; mean dHbO=0.92, CI₉₅=0.91, P=0.071; mean dHb=0.10, CI₉₅=0.21, P=0.297). The HbT and HbO showed a substantially smaller increase in the placebo group (mean dHbT=0.31, CI₉₅=0.74, P=0.22; mean dHbO=0.57, CI₉₅=0.80, P=0.094) while the Hb decreased (mean dHb=−0.26, CI₉₅=0.29, P=0.05). Comparing to the placebo group Hb increased significantly in the VP group (P=0.027) while the increase of HbO and HbT did not reach the level of significance (P=0.29 and 0.11). DSI showed a significantly larger increase in the VP than in placebo group (dDSI=25.8 CI₉₅=8.8 [VP]; dDSI=3.3, CI₉₅=3.7 [Placebo], P<0.005). The CBFV and PI did not differ significantly between groups. (dVm=5.0±2.98 cm/s [VP], dVm=4.1±2.57 cm/s [Placebo], P=0.28; dPI=0.08 [VP], dPI=0.09 [Placebo]; P=0.47).  

Conclusion: VP increases cerebral perfusion and parenchymal oxygen extraction as well. The increased perfusion was indicated by NIRS and by TCD measurement of DSI while conventional velocity and pulsatility measurements failed to detect theses effects. NIRS is a sensitive, feasible method of measuring changes in regional blood flow and tissue oxygenation in the superficial cortex.