Stroke and its disability have deserved the notoriety of a severe and potentially lethal condition, whose treatment is still challenging. The widely craved result of saving as much as possible from the neural tissue and eventually reviving what is thought to be in the ischemic penumbra – if not already dead and gone – is the outcome every clinician is dreaming of. There are several reviews on the issue, which have discussed several options of achieving neuroprotection in acute ischemic stroke. Of course, reviews are not and do not pretend to be exhaustive; new drugs enter repeatedly in the scene. We would limit our comments on some of the pharmacological agents, that although seem to be worldwide available, are still looking for obtaining the citizenship in the therapeutic armamentarium of acute ischemic stroke.

A methodological clarification should be done right at the start, since the final outcome while treating a stroke patient, needs some quantification. Several scales of invalidity and morbidity are available. While talking about neuroprotection in acute (again: acute) stroke, it is clearly we are aiming to decrease the width of neural tissue injury. Yet the target group (patient demographics) is very inhomogeneous. Comorbidities are numerous and diverse. Use of other pharmacological agents is abundant and not without implications. Hence the need for a strong experimental basis to measure the efficacy of a potential neuroprotective agent. Let alone the fact that translation of experimental data into their proven effects on humans is a complicated road map, with ethical and skeptical deterrents.

We have selected three chemical names of some relatively unknown preparations, considered as neuroprotectants and neuroprotective therapy and searched on PubMed with the combination of terms “name of the drug” and “stroke”. The search was made based on the most recent papers (until the date 26 August 2024), and five most recent papers for each from the following drugs were included:

3-N-Butylphthalide (total mentions: 524 articles)

Edaravone dexborneol (total mentions: 39 articles)

Nerinetide (total mentions: 45 articles)

Large group of agents (for example, potential therapeutic agents targeting NVU) were not part of this commentary. Other potentially active drugs in this field include Sevoflurane (>11600 articles), a well-known anesthetic. Also, substance P (>26000 articles) has been largely studied in the field of neurotransmission and pain and these two agents were not part of our commentary. Ferrostatin-1 (total mentions: 1024 articles) and Clormethiazole (clomethiazole: 974 articles) were also not part of this commentary, for their scope of pharmacological activity is much more wide than merely ischemic stroke. A pioneering paper of Lancet (2020) quoted from a recent source was as well mentioned in the references here below.

Toxic neuroinflammation, mitochondrial homeostasis and caspase pathways are among the mentioned mechanisms [2, 3, 4]. Zhou et al had a study group of eighty-six patients [2]. The other studies mentioned in the Table 1 above, were all conducted with mice and monkeys.

Scavenging of free radicals, anti-inflammatory properties and cytoprotection after all, are among the mechanisms reputed to edaravone [7, 8, 9, 10, 11]. There is an ongoing large scale and multi-center trial (TASTE-2), that will enhance optimism to this preparation [9].

There are also several studies on nerinetide, and its potential benefits on ischemic stroke; ESCAPE-NA1 presented the initial results on 2020 but still guidelines are needed [12, 13, 14, 15, 16].

Regarding the same drug, reviews are available, still raising uncertainties while promoting optimism [13, 14].

There is an obvious need towards the optimization of clinical trial protocols [1]. The first two neuroprotectants that are mentioned here above come out mostly or exclusively from Chinese authors and sources; hence the need for raising awareness in other settings. Their use in the next future (namely of N-butyl-phthalide and edaravone) is beyond all doubts, of great interest to clinicians treating stroke and cerebral ischemia.

Obviously, it is hard to extrapolate pre-clinical studies (experimental; animal data) into plausible, convincing clinical outcomes [17, 18]. As a source pointed out, successful bench-to-bedside translations are still lacking [18]. Nevertheless, expert opinions are still of high value, and might guide individual patients’ treatment; provided safety and familiarity with certain drug(s) is ensured. A question of time more than a question of economy and availability, obviously.