Pharmacological Characterizations of anti-Dementia Memantine Nitrate via Neuroprotection and Vasodilation in Vitro and in Vivo

Abstract

We have previously designed and synthesized a series of novel memantine nitrates, and some of them have shown neuroprotective effects; however, the detailed mechanisms remain unknown. In this study, we demonstrated that MN-12, one of the memantine nitrates, concentration-dependently protected against glutamate-induced neurotoxicity in rat primary cultured cerebellar granule neurons (CGNs). Western blotting assays revealed that MN-12 might possess neuroprotective effects through the inhibition of ERK pathway and activation of PI3K/Akt pathway concurrently. Moreover, MN-12 concentration-dependently dilated precontracted rat middle cerebral artery through activation of NO−cGMP pathway ex vivo. In the 2-vessel occlusion (2VO) rat model, MN-12 alleviated the impairments of spatial memory and motor dysfunction possibly via neuroprotection and improvement of the cerebral blood flow. Furthermore, the results of preliminary pharmacokinetic studies showed that MN-12 might quickly distribute to the major organs including the brain, indicating that MN-12 could penetrate the blood−brain barrier. Taken together, MN-12 might provide multifunctional therapeutic benefits for dementia associated with Alzheimer's disease, vascular dementia, and ischemic stroke, via neuroprotection and vessel dilation to improve the cerebral blood flow.

Dual-Functional MN-08 Attenuated Pulmonary Arterial Hypertension Through Vasodilation and Inhibition of Pulmonary Arterial Remodeling

“…[23][24][25][26] Preliminary pharmacological screening revealed that some of these novel memantine nitrates have significant vasodilative effects in vitro. 27,28 Recently, we demonstrated that MN-08 (structure as shown in Figure S7A in the Data Supplement), one of the representative memantine nitrates, was simultaneously able to antagonize NMDARs and release NO to dilate blood vessels, ameliorating brain injury, and vasospasm in subarachnoid hemorrhage models. 29 MN-08 attenuated LPS (lipopolysaccharide)-induced acute lung injury in rats by inhibiting the inflammatory response.…”

Sustainable Release of Propranolol Hydrochloride Laden with Biconjugated-Ufasomes Chitosan Hydrogel Attenuates Cisplatin-Induced Sciatic Nerve Damage in In Vitro/In Vivo Evaluation

“…Recently, studies demonstrated that propranolol revealed significant suppression of p38 protein expression that primarily regulates cell proliferation, migration, cell differentiation, and BCL-2 family, inhibiting apoptosis [ 182 , 183 ]. In addition, BCl-2 is considered a tissue homeostasis indicator in vascular, heart, and neurodegenerative diseases [ 184 , 185 ]. Additionally, several studies reported the role of hyperglycemia-induced peripheral neuropathy associated with decreased BCl-2, increased Bax, cleaved caspase-3, and cell apoptosis [ 186 , 187 , 188 ].…”

Neuroprotection against 1-Methyl-4-phenylpyridinium-induced cytotoxicity by naturally occurring polydatin through activation of transcription factor MEF2D

“…The cell viability was assessed by the MTT test as described [17]. CGNs were pretreated with polydatin (3, 10, 30 and 100 µM) for 2 h, followed by 75 µM MPP + stimulation for 24 h. To determine the neuroprotective effects of polydatin with the increase of MPP + incubation time, CGNs were pretreated with 100 µM polydatin for 2 h, and then challenged by 75 µM MPP + for different lengths of time.…”