The dual‐functional memantine nitrate MN‐08 alleviates cerebral vasospasm and brain injury in experimental subarachnoid haemorrhage models

Abstract

Background and Purpose Cerebral vasospasm and neuronal apoptosis after subarachnoid haemorrhage (SAH) is the major cause of morbidity and mortality in SAH patients. So far, single‐target agents have not prevented its occurrence. Memantine, a non‐competitive NMDA re3ceptor antagonist, is known to alleviate brain injury and vasospasm in experimental models of SAH. Impairment of NO availability also contributes to vasospasm. Recently, we designed and synthesized a memantine nitrate MN‐08, which has potent dual functions: neuroprotection and vasodilation. Here, we have tested the therapeutic effects of MN‐08 in animal models of SAH. Experimental Approach Binding to NMDA receptors (expressed in HEK293 cells), NO release and vasodilator effects of MN‐08 were assessed in vitro. Therapeutic effects of MN‐08 were investigated in vivo, using rat and rabbit SAH models. Key Results MN‐08 bound to the NMDA receptor, slowly releasing NO in vitro and in vivo. Consequently, MN‐08 relaxed the pre‐contracted middle cerebral artery ex vivo and increased blood flow velocity in small vessels of the mouse cerebral cortex. It did not, however, lower systemic blood pressure. In an endovascular perforation rat model of SAH, MN‐08 improved the neurological scores and ameliorated cerebral vasospasm. Moreover, MN‐08 also alleviated cerebral vasospasm in a cisterna magna single‐injection model in rabbits. MN‐08 attenuated neural cell apoptosis in both rat and rabbit models of SAH. Importantly, the therapeutic benefit of MN‐08 was greater than that of memantine. Conclusion and Implications MN‐08 has neuroprotective potential and can ameliorate vasospasm in experimental SAH models.

Therapeutic efficacy of novel memantine nitrate MN‐08 in animal models of Alzheimer’s disease

“…These compounds would simultaneously inhibit NMDA receptors and release NO in the brain. Our previous study has confirmed that MN-08 was able to dilate cerebral blood vessels and improve the CBF by binding NMDA receptors to release NO, ameliorating brain injury and cerebral vasospasm in SAH models (Luo et al, 2019).…”

“…MN-08 is thus less toxic than memantine. Moreover, our previous studies also found that MN-08, despite containing a nitrate group, avoided causing side effects related to systemic hypotension while increasing cerebral blood flow (Luo et al, 2019). This unique trait may be attributable its PK characteristics: MN-08 was rapidly absorbed and distributed into various tissues and organs, and the concentration of MN-08 in brain tissue was much higher than that in the plasma.…”

“…Unsuspectedly, memantine nitrates performed in a superior fashion to memantine in treatment of a rat model of stroke (Takahashi et al, 2015; Wang et al, 2006). Recently, we demonstrated that one of the novel memantine nitrates, MN‐08 (structure as shown in Figure 1a), can bind NMDA receptors to release NO, dilate cerebral blood vessels and increase cerebral blood flow, subsequently ameliorating brain injury and cerebral vasospasm in experimental subarachnoid hemorrhage models (Luo et al, 2019); MN‐08 does not, however, change blood pressure in normal rats, lowering the risk of systemic hypotension induced by traditional nitrate drugs (Luo et al, 2019). The effect of MN‐08 on AD is still unclear.…”

25-Hydroxycholesterol protecting from cerebral ischemia-reperfusion injury through the inhibition of STING activity

“…This disease causes physical disability and serious cognitive damage, often requiring immediate treatment. Moreover, patients undergoing cerebrovascular surgery (e.g., intervention and aneurysm clipping) are at risk of cerebral ischemia due to vasospasm [ 1 ]. If cerebral ischemia occurs, the perfusion process is significantly reduced, and the cell starts to swell and die.…”

Memantine protects blood–brain barrier integrity and attenuates neurological deficits through inhibiting nitric oxide synthase ser1412 phosphorylation in intracerebral hemorrhage rats: involvement of peroxynitrite-related matrix metalloproteinase-9/NLRP3 inflammasome activation

“…Large amounts of glutamate is released during the pathophysiology of distinct CNS disorders, leading to NMDAR stimulation [ 17 ]. Memantine, the NMDAR antagonist, has recently demonstrated a powerful brain-protective effect in the treatment of disparate CNS diseases such as cerebral ischemia [ 18 , 19 ], infantile rat hydrocephalus [ 20 ], traumatic brain injury [ 21 , 22 ] and subarachnoid hemorrhage [ 16 , 23 ]. Overactivation of the complex of NMDAR, postsynaptic density protein 95 and nNOS produces large amounts of nitric oxide and superoxide anions (O 2 − ), ultimately leading to the result of peroxynitrite formation [ 3 , 24 ].…”