**1. Introduction**

Parkinson's disease (PD) is a neurodegenerative disease characterized by the selective loss of dopaminergic (DA) neurons and the formation of Lewy bodies in the brain. The mainly symptoms was movement disorders such as bradykinesia, myotonia, tremors and abnormal gait [1]. Many reasons such as apoptosis, oxidative stress, genetic factors, environmental factors, mitochondrial dysfunction, ubiquitin-proteasome system dysfunction, immune abnormalities, excitotoxicity and cytotoxicity of calcium may be related to the occurrence of PD [2,3]. Many studies have shown that DA neuron apoptosis has an important effect on the pathogenesis of PD, the number of apoptotic cells in PD patients is nearly 10 times more than normal aged person [4]. However, the exact cause of DA neuron apoptosis is unknown [5]. Oxidative stress, loss of antioxidant function and mitochondrial function damage, can induce DA neuron apoptosis at different levels [6]. The inhibition of pro-apoptotic protein Bax and anti-apoptotic protein Bcl-2 can regulate the apoptosis of DA neurons [7]. Therefore, regulation the expression of apoptosis-associated genes and proteins has become another strategy for the treatment of PD.

The PI3K–Akt pathway plays an important role in neuronal survival and death. Activation the PI3K–Akt pathway can inhibit the activity of downstream caspase-3 and thus inhibit the apoptosis of DA neurons, which can be weakened by the PI3K-specific inhibitor LY294002 [8]. Studies found pretreatment with simvastatin, sulforaphane, erythropoietin,β-interferon and catechins on 6-OHDA-damaged SH-SY5Y cells can increase the PI3K phosphorylation and directly activates the PI3K signaling pathway. Activated Akt can inhibit the activity of downstream caspase-3 and thus inhibit the apoptosis of DA neurons, which can be weakened by the PI3K-specific inhibitor LY294002 [9]. The brain tissues of PD patients and normal people were analyzed by immunofluorescence and western blotting after death. It was found that Akt and activated phosphoSer473-Akt were significantly reduced in the brains of PD patients. Nerve growth factor (NGF) plays an important role in the stages of neuron growth and development, axon growth, transmitter synthesis and cell apoptosis. Studies have shown that the application of corresponding treatments after spinal cord ischemia can induce NGF to activate the PI3K–Akt pathway to inhibit neuronal apoptosis. It can be seen that increase NGF to activate the PI3K–Akt pathway to inhibit DA neuronal apoptosis is a new strategy for the prevention and treatment of PD.

Marine seaweeds produce and accumulate a large number of substances with special chemical structures, physiological activities and functions during their growth and metabolism. The development and utilization ofmarine biologic resourcesis animportant area and direction for drug candidates. Themain feature of the polysaccharides extracted from seaweeds is that it contained sulfated groups. The structures were more complex and the activities were more excellent compared with the polysaccharides extracted from the land plants [10]. Fucoidan is a kind of sulfated polysaccharide extracted from brown algae. It has various biologic activities such as antivirus, antitumor, antimutation, antiradiation and immunity enhancement [11]. The bioactivity such as antioxidant, anticoagulation, neuro-protective activity of fucoidan depends on several structural parameters such as the degree of sulfation (DS), the molecular weight, other substitution groups and position, type of sugar and glycosidic branching. Our preliminary study had shown that the fucoidan with highest sulfated group exhibited stronger activity in scavenging superoxide radical and also hydroxyl radical [12]. The sulfated and benzoylated derivatives of fucoidan could enhance the neuroprotective activity by increasing mitochondrial activity and decreasing LDH and ROS release induced by 6-OHDA (*p* < 0.01 or *p* < 0.001) [13]. Our previous studies found that fucoidan (FPS) can reduce DA neurons damage in phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model [14,15]. FPS has a protective effects on oxidative damage and inflammatory lesion on DA neurons caused by MPTP in PD mouse, [16]. FPS is a crude polysaccharide prepared from *Saccharina japonica*. After degradation and purification, we go<sup>t</sup> three fractions with different sulfated groups and monosaccharides compositions. Among the samples, UF with highest uronic acid and lowest sulfated groups has the strongest neuroprotective effect both in vitro and in vivo [17]. UF can increase the level of antioxidant enzymes and reduce the level of lipid peroxidation in PD mice [18]. We further found that UF can upregulate the expression of the anti-apoptotic protein Bcl-2, reduce the expression of the pro-apoptotic protein Bax, and significantly inhibit the apoptosis of DA neurons in H2O2–induced SH-SY5Y cell model [13]. Therefore, we speculate that UF has effect on the DA neurons apoptosis. However, it is not ye<sup>t</sup> established whether UF exhibited apoptosis activity through PI3K–Akt pathway in a MPP<sup>+</sup> induced neuronal cell line. Can UF activate PI3K by acting on the NGF to cause progressive activation of the PI3K–Akt pathway? How does UF regulate downstream signaling molecules and proteins in the PI3K–Akt pathway?

The aim of this study is to clarify whether UF can activate the PI3K–Akt pathway by acting on NGF protein and illuminate the anti-apoptosis mechanism of UF through the PI3K–Akt pathway. This study will provide experimental foundation and theoretical basis for the application of UF in PD therapy and provide a scientific basis for the development of new and e ffective anti-PD marine drugs.
