Despite the number of advances in treatment and care, stroke remains the second most common cause of mortality and disability worldwide, while in the Philippines, cerebrovascular disease is third among all causes of death [1–3]. Based on type, strokes are divided into ischemic and hemorrhagic strokes with ischemic strokes occurring more frequently of the two. In the Philippines, ischemic strokes make up 63% of all stroke types [4]. In the most recent years, the field of stroke medicine has theoretically achieved the pinnacle of treatment of ischemic strokes by way of thrombolysis and mechanical thrombectomy. Currently, these are the cornerstones in the acute management of ischemic stroke with Class I Level A recommendation [5]. Yet, despite such miraculous advances in stroke care, a great majority of patients are unable to receive such treatments due to delayed arrival to capable facilities or lack of able facilities at all. Considering both developed and underdeveloped countries, 65% to up to 85% of patients present beyond the golden period for recombinant tissue plasminogen activator (rtPA) which is 4.5 h [6–9]. After thrombolysis and mechanical thrombectomy, the standard of stroke care is severely lacking in regard to functional recovery with long-term goals relying mostly on secondary prevention strategies against stroke recurrence through the use of statins, anti-platelets, anticoagulants, and control of risk factors, and physical rehabilitation to improve functionality [5].

Neuroprotective agents have been developed and used over the years in the hope of being the panacea for neurological diseases, especially stroke. These medications were designed to improve neuronal survival by their mechanisms of action which include reducing neuronal injury through improving neuronal membrane integrity for cytidine-5’-diphosphocholine (CDP-choline), reducing oxidative stress and inflammation by scavenging reactive oxygen species and other substances causing oxidative stress for edaravone, and, with the newer drugs cerebrolysin and MLC601, by promoting neuronal regeneration and synaptogenesis [10–13]. Among the neuroprotective agents available today in Asia, CDP-choline, cerebrolysin, edaravone, and MLC601 are the most studied in relation to short and long-term stroke recovery. In spite of the pharmacological potential and number of studies involving neuroprotectants, guidelines do not highly recommend the use of such agents classifying them at Class 3 Level A strength of evidence [5].

CDP-choline is also known commercially as citicoline (Figure 1). This is a naturally occurring compound which is a precursor of the neurotransmitter, acetylcholine, and drives the production of phosphatidylcholine which is a component of the cell membrane of the neuron. The active component of CDP-choline works as an antioxidant and anti-inflammatory and influences and modulates the neurotransmitter balance in the central nervous system [10].

Cerebrolysin (Figure 2) is a peptide-based nootropic drug derived from porcine brain proteins, composed of low-molecular weight peptides and free amino acids which can penetrate the blood-brain-barrier and act centrally as a neuroprotective agent with anti-inflammatory and antioxidant properties, and neurorestorative properties by activating brain derived neurotropic factor and nerve growth factor to activate neuronal stem cells to mature into neurons that can replace those damaged by stroke. This drug also improves energy metabolism and enhances synaptic plasticity [11].

Edaravone is an organic molecule with a pyrazolone structure, chemical formula C₁₀H₁₀N₂O, and its chemical name is 3-methyl-1-phenyl-2-pyrazolin-5-one (Figure 3). It is a reactive oxygen species scavenger and, thus, has antioxidant and anti-inflammatory effects and gives it its neuroprotective properties as well as the ability to stabilize and protect the blood-brain-barrier [12].

MLC601 is a combination of plant extracts from the plants Astragalus membranaceus, Ligusticum wallichii, Panax ginseng, Panax notoginseng, and Pueraria lobata which all have antioxidant, anti-inflammatory, neuro-, and cardio-vascular protective properties. Studies of this drug have shown both neuroprotective and neurorestorative capabilities [13].

The primary goal of this study is to revisit the major trials for each of these neuroprotectants with the aim of highlighting the gravity of the benefits of these medications as a class in the overall functional recovery of patients with ischemic strokes, and thus help validate their utilization in stroke management.

The primary objective of this study is to evaluate the degree of effect of the pharmacologic neuroprotectants CDP-choline, cerebrolysin, edaravone, and MLC601 in the functional recovery of patients with ischemic strokes. The secondary objective is to describe the safety of administering neuroprotectants in ischemic strokes.

The following databases were utilized for extensive literature search: PubMed (1976 to June 2020); PMC (January 1980 to June 2020); Ovid (1982 to June 2020) and Cochrane (1980 to 2020). A comprehensive search strategy was used with the following terms “CDP-choline”, “cerebrolysin”, “MLC601”, and “edaravone” each combined with the term “acute ischemic stroke”. The search strategy was adapted for each database in order to achieve more sensitivity and improve the quality of yielded studies. The references of relevant publications found by the search were screened for further studies which may be included in the analysis.

Literature search using the PubMed, PMC, Ovid, and Cochrane online search engines yielded a total of 2,025 studies with 297 studies for cerebrolysin, 542 for CDP-choline, 1,109 for edaravone, and 77 for MLC601. Of these initial search outcomes, 24 studies were retained and further scrutinized for inclusion in the analysis. After application of the inclusion and exclusion criteria, 24 studies were selected for evaluation. After further deliberation on the details of these 24 studies, the number of included studies was reduced to 15 with 5 studies for cerebrolysin, 4 studies for CDP-choline, 3 studies for edaravone, and 3 studies for MLC601 which were included in the final statistical analysis. A flow diagram describing this process is presented in Figure 4. A summary of the included studies is presented in Table 1.

The 15 studies included in the final analysis were all blinded, randomized, placebo-controlled trials with a neuroprotectant pitted against a placebo control with patients receiving the standard of care for acute ischemic infarct which included any or all of the following: anti-platelet medications, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, rtPA, and physical therapy or rehabilitation. Of the included studies the oldest was published in 1999 and the most recent in 2019. The inconsistency index (I²) was used to measure heterogeneity of the studies included resulting in an index of 70%.

A total of 7,828 participants were noted in the 15 studies included with all patients above the age of 18 years diagnosed with an acute ischemic stroke ranging from mild to moderate severity based on the baseline NIHSS scores. In all the studies, initiation was started within 72 h of symptom onset except for one that started treatment within 90 days from symptom onset. Follow-up was continued for at least 14 days from the initiation of treatment and as long as 24 months thereafter with most studies having a final follow-up at 90 days. All studies were done pitting a neuroprotectant against a placebo with all participants receiving the standard of care appropriate for their stroke during the study period. Safety was evaluated in all studies as well.

The measure of the primary endpoint was varied among the studies but the common factor measured was the change in the functionality of the participants during the study period using validated, widely utilized, and objective scales (e.g., NIHSS, modified Rankin Scale, Barthel Index score, Fugl-Meyer Assessment). Secondary endpoints measured in these studies were related to either other forms of functional outcome measures or safety outcomes (e.g., adverse events, serious adverse events, death rates).

This study provides a quantitative summary of valid and high-quality clinical studies performed in qualified centers. The summary of the analysis is presented in a forest plot in Figure 5. Analytical results show that the outcome of patients with acute ischemic strokes improved significantly when receiving neuroprotectants versus placebo [OR = 0.29 (0.09–0.50); confidence interval (CI) = 95%]. The significance of the efficacy of neuroprotectants in stroke recovery is further supported by the P-values calculated at 0.0022 for the one-tailed test and 0.0030 for the two-tailed test; both being < 0.005.

Another analysis was done excluding the study by Dávalos et al. [21] for CDP-choline. This is the International Citicoline Trial on acUte Stroke (ICTUS) trial, the largest study for CDP-choline to date which propelled CDP-choline into popularity when it was first introduced in the market. But despite this, experts deduced that the results of this study were heavily influenced by the peak in the use of rtPAs for acute cerebral infarcts. Thus, to reduce the influence of rtPA in the analysis of our data, we recalculated the data excluding this study and the results can be seen in Figure 6. The significance of the efficacy of neuroprotectants in stroke recovery remains significantly in favor of their use as the P-values are 0.0018 for the one-tailed test and 0.0036 for the two-tailed test [OR = 0.32 (0.11–0.53); CI = 95%].