NP10679: A new horizon for neuroprotection in aneurysmal subarachnoid hemorrhage

Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening cerebrovascular disease affecting young individuals in their working years. aSAH occurs when an aneurysm, a weaken area in a brain blood vessel, bursts and bleeds into the space surrounding the brain, between the arachnoid membrane and the pia mater, and sometimes in the brain parenchyma and ventricles (Macdonald and Schweizer, 2017). A major complication of SAH, which can result in permanent disability or death, is the delayed neurological deterioration that occurs in over one-third of patients during the week following aneurysm rupture. This phenomenon is attributed to the occurrence of vasospasm, the narrowing of a brain blood vessel, which leads to delayed cerebral ischemia (DCI) (Bershad and Suarez, 2021). Despite advances in clinical diagnosis and surgical interventions, nimodipine, a dihydropyridine l-type cerebroselective calcium channel antagonist, remains the only universally recommended and Food and Drug Administration-approved drug to manage vasospasm and counteract DCI (Hoh et al, 2023; Caylor and Macdonald, 2024). Nevertheless, nimodipine has several limitations, and the search of more effective drugs is an active area of ongoing preclinical and clinical research (Luzzi et al, 2024). Wang et al (2025) present data demonstrating the therapeutic potential of the pH-sensitive GluN2B-selective N-methyl-D-aspartate receptor (NMDAR) inhibitor NP10679 for the treatment of aSAH-associated vasospasm and DCI.

Cerebral damage after SAH occurs in 2 phases. Early brain injury develops within the first 72 hours after SAH and is caused by transient global ischemia and toxic effects of subarachnoid blood triggering microcirculatory dysfunction, blood-brain barrier breakdown, neuroinflammation, oxidative cascades, cerebral edema, and neuronal cell death (Lauzier et al, 2023). In addition, 3–14 days after SAH, surviving patients can experience further neurological deterioration due to DCI (Macdonald and Schweizer, 2017). Excessive release of glutamate after aSAH is a major determinant of neuronal death (Nagel et al, 2009; Yang et al, 2021; Tholance et al, 2023). Supraphysiologic levels of glutamate activate excitatory receptors, including NMDARs, and induce an overload of cytosolic Ca²⁺ that ultimately results in the activation of lethal signaling pathways (Dirnagl et al, 1999). However, despite the central role that excitotoxicity plays in the pathophysiology of cerebral ischemia, clinical trials testing the neuroprotective effect of NMDAR antagonism have all failed (Ikonomidou and Turski, 2002; O'Collins et al, 2006).

NMDARs are heteromeric receptors with 2 essential GluN1 subunits and 2 GluN2 subunits or 2 of the relatively rare GluN3 subunits. GluN2 and GluN3 subunits confer distinct electrophysiological and pharmacological properties on the receptors, conveying unique signaling pathways (Hansen et al, 2021). GluN2A and GluN2B subtypes are predominantly expressed in the adult forebrain (Wyllie et al, 2013), and have been shown to mediate neuronal survival and death, respectively (Ge et al, 2020). The major role of NMDARs in brain functioning, their complex regulation, and the lack of high specific-subtype drugs explain why nonselective NMDAR antagonists have a number of off-target adverse central nervous system effects, including hallucinations, increase in blood pressure, and even catatonia at high doses (Seillier et al, 2022). On the other hand, and as pointed by Wang et al (2025) on-target side effects of selective NMDAR antagonists in noninjured brain regions are probably the main reason of their inefficacy in clinical trials. These effects may lead to cognitive impairment, motor dysfunction, and psychotomimetic effects, leading to the administration of suboptimal doses of antagonists which reduce their therapeutic potential in humans (Wu and Tymianski, 2018).

With the goal of overcoming this major limitation, the authors evaluated the effect of NP10679, a pH-dependent NMDAR inhibitor, which appears to be a clinically suitable candidate to treat DCI. NP10679 is a selective inhibitor of GluN2B-NMDAR subtype, a receptor type itself sufficient to provoke a Ca²⁺ overload able to induce death cell (Liu et al, 2007).

Over the years, selective GluN2B-NMDAR antagonists have emerged as highly neuroprotective in animal models of stroke and other neurodegenerative diseases (Lai et al, 2014). However, because of their adverse on-target effect, their clinical development has not been further pursued (Liu et al, 2020). The pH-sensitive NP10679 inhibitor could represent a major step in the optimization of these antagonists for clinical use. Indeed, NP10679 has higher potency at acidic extracellular pH levels, as those found in the ischemic tissue, than at physiological pH, reducing the potential antagonism of NMDARs in the healthy brain (Myers et al, 2021; Zaczek et al, 2023) (Fig. 1). Furthermore, in another study, the same group has recently reported that NP10679 is well tolerated in healthy humans (Zaczek et al, 2023).

Fig. 1.

Molecular mechanisms of NP10679-mediated neuroprotection in aSAH. pH-sensitive GluN2B-selective NMDAR antagonist NP10679 only binds neuronal Glu2Nb subunit receptors at acidic levels of extracellular pH found in ischemic brain regions, blocking excitotoxicity. NP10679 does not bind neuronal Glu2Nb-NMDARs at physiological pH, as in healthy tissue, allowing normal glutamatergic neurotransmission. NP10679 could also potentially bind Glu2Nb-NMDARs in endothelial cells (EC) alleviating vasoconstriction. Nimodipine, the standard treatment for aSAH, blocks l-type cerebroselective calcium channel (LTCC) in vascular smooth muscle cells (VSMC) reducing vasospasm, and thus, combined therapy of NP10679 with nimodipine has a synergistic neuroprotective effect. Created in https://BioRender.com.

Considering that nimodipine is the standard treatment for aSAH, to start, the authors evaluated the hemodynamic effects of NP10679 either alone or in combination with nimodipine and found that, after experimental SAH, NP10679 did not affect arterial blood pressure. These results are highly relevant because nimodipine can cause serious hypotension (Hajizadeh Barfejani et al, 2019). Next, the authors tested whether NP10679 is neuroprotective in an aSAH mouse model. NP10679, both at low (2 mg/kg) and high (5 mg/kg) doses, improved neurological deficits and motor function without affecting hemorrhage size. More importantly, these effects were potentiated when NP10679 was combined with nimodipine. Nimodipine acts primarily on vascular smooth muscle cells by blocking voltage-gated l-type calcium channels, preventing calcium influx and vasoconstriction, which could alleviate vasospasm. Therefore, combined therapy of NP10679 and nimodipine has the potential to act synergically counteracting DCI injury (Fig. 1) (Carlson et al, 2020).

Once the neuroprotective effect of NP10679 was established, the authors explored the pharmacokinetics of NP10679 in mice, rats, and dogs. The authors demonstrated that NP10679 had a high plasma protein binding, low predicted hepatic clearance, and a relatively long mean half-life. In addition, the clearance of either NP10679 or nimodipine was not altered when the drugs were coadministered. Lastly, based on the toxicokinetic and efficacy data collected from the animal models, and applying allometric scaling, the authors predict the optimal therapeutic dose in humans to be around 0.5 mg/kg.

The study has several strengths. First, the pH-dependent effects of NP10679 may overcome the downsides of previous NMDAR-based therapies. Second, the study provides experimental evidence indicating that NP10679 improves long-term neurological function even when its administration is interrupted 3 days after SAH. This finding indicates that NP10679 dampens acute excitotoxicity induced by glutamate-dependent NMDAR activation, preventing subsequent neurological deterioration rather than just alleviating symptomatic neurological outcomes. Third, the study methodically addressed hemodynamic and pharmacokinetic interactions between NP10679 and nimodipine, the gold standard of aSAH care.

A noteworthy finding of the study is the ability of NP10679, albeit at high doses, to alleviate the SAH-induced vasospasm. Because NP10679 did not affect hemorrhage volume, the reduction of arterial constriction cannot be explained by other pathological changes, including the release of oxyhemoglobin from lysed erythrocytes (Macdonald and Weir, 1991). According to the authors, the effect could be dependent on either an indirect effect of neuronal NMDAR on cerebral blood vessels or on a direct antagonism of NMDAR expressed on endothelial cells (Fig. 1) (Hogan-Cann et al, 2019; Anfray et al, 2020). Indeed, brain endothelial cells have been reported to express GluN2B-NMDAR and to be involved in the regulation of cerebral blood flow (Andras et al, 2007). However, because activation of endothelial NMDARs increases cerebral blood flow, it would be expected that NP10679, by blocking NMDAR, should not induce vasodilation (LeMaistre et al, 2012; Anfray et al, 2020). Thus, the contribution of neuronal and/or endothelial GluN2B-NMDAR on cerebrovascular function will have to be further elucidated. Similarly, their role in mediating cerebrovascular dysfunction in pathological conditions will have to be examined in future studies.

On another note, although assessment of neurological function is central in evaluating the potential neuroprotective effect of a SAH therapeutic intervention, future studies will have to assess the effect of NP10679, alone or in combination with nimodipine, on the neuronal loss associated with post-SAH DCI.

In conclusion, the search of effective therapeutic drugs for SAH-related neurological dysfunction remains a major challenge. Despite DCI being one of the most serious complications of SAH, its delayed presentation offers a time window for potential treatments. Wang et al (2025) show data in support of the therapeutic potential of NP10679 in the clinical management of DCI. The high selectivity of NP10679 for GluN2B-NMDAR and the strong preclinical evidence demonstrating NP10679 efficacy in improving neurological function support further efforts to better characterize NP10679 in disease animal models and potentially in humans.

Conflict of interest

The authors declare no conflicts of interest.