dl-3-n-Butylphthalide prevents neuronal cell death after focal cerebral ischemia in mice via the JNK pathway

Abstract

dl-3-n-Butylphthalide (NBP) has shown cytoprotective effects in animal models of stroke and has passed clinical trails as a therapeutic drug for stroke in China. Hence, as a potential clinical treatment for stroke, understanding the mechanism(s) of action of NBP is essential. This investigation aimed to delineate the cellular and molecular mechanism of NBP protection in neuronal cultures and in the ischemic brain. NBP (10 M) attenuated serum deprivation-induced neuronal apoptosis and the production of reactive oxygen species (ROS) in cortical neuronal cultures. Adult male 129 S2/sv mice were subjected to permanent occlusion of the middle cerebral artery (MCA). NBP (100 mg/kg, i.p.) administrated 2 hrs before or 1 hr after ischemia reduced ischemia-induced infarct formation, attenuated caspase-3 and caspase-9 activation in the ischemic brain. TUNEL-positive cells and mitochondrial release of cytochrome c and apoptosis-inducing-factor (AIF) in the penumbra region were reduced by NBP. The pro-apoptotic signaling mediated by phospho-JNK and p38 expression was down-regulated by NBP treatment in vitro and in vivo. It is suggested that NBP protects against ischemic damage via multiple mechanisms including mitochondria associated caspase-dependent and -independent apoptotic pathways. Previous and current studies and recent clinical trials encourage exploration of NBP as a neuroprotective drug for the treatment of ischemic stroke.

3-N-Butylphthalide (NBP) Attenuates the Amyloid-�-Induced Inflammatory Responses in Cultured Astrocytes via the Nuclear Factor-κB Signaling Pathway

“…NBP exhibits protective effects against focal cerebral ischemia in animal models through the prevention of mitochondrial damage, the inhibition of neuronal apoptosis, the improvement of cerebral blood flow, and the reduction of infarct volume [21,22,23]. Our previous studies demonstrated that NBP could significantly inhibit caspase-3-mediated apoptosis after cerebral ischemia in diabetic rats [24]; and NBP administration could attenuate stroke-induced neuron loss and activation of astrocytes in diabetic rats [25].…”

Visualizing Cell Death in Experimental Focal Cerebral Ischemia: Promises, Problems, and Perspectives

“…In focal cerebral ischemia, TUNEL has been widely used, often as the only measurement to assess apoptosis after stroke (Figure 4). After MCAO in mice or rats, TUNEL-positive cells can be found already 1 hour after occlusion (Linnik et al, 1995), reach their peak by 24 hours (Li et al, 2010), but are still detected after 28 days (Zhang et al, 2010a). Despite the uncertainty regarding the specific type of cell death, TUNEL is still the method of choice for identification of DNA fragmentation.…”

Isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP and 10-hydroxy-NBP, across the rat blood-brain barrier

“…Racemic NBP was approved for marketing in China by the Chinese Food and Drug Administration (CFDA) in 2004 [1,2] . Pharmacological studies have revealed that NBP exerts neuroprotective effects by increasing blood flow in the cerebral ischemic area and inhibiting the release of 5-hydroxytryptamine, glutamate and cytochrome c through the c-Jun N-terminal kinase pathway [3][4][5][6] . Recent studies have also demonstrated that NBP attenuates oxidative stress and improves neutral morphology after chronic cerebral ischemia [7] .…”