Neurodegenerative disease is a progressive and fatal disorder caused by chronic dysfunction in the central nervous system (CNS). Patients with neurodegenerative diseases often suffer from intolerable and untreatable frailty. Although the detailed etiological causes of the neurodegenerative disorder generally remain vague and the clinical manifestations are differentiated, their molecular pathogeneses share common underlying factors, such as unbalance of neurotransmitters, abnormal protein aggregation and misfolding, neuroinflammation and oxidative stress, interference in metal homeostasis, etc. [[1], [2], [3], [4], [5]].

Phosphodiesterases (PDEs) are a superfamily of enzymes responsible for hydrolyzing two second messengers: cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) [6]. These two second messengers play a crucial role in triggering intraneuronal signaling cascades [7]. Adenylate and guanylate cyclase (AC and GC) catalyze the synthesis of cAMP and cGMP starting from ATP and GTP, respectively. The increase in intracellular cAMP and cGMP levels activated their specific protein kinases (PKA and PKG) through phosphorylation of diverse substrates, thereby regulating different intracellular processes [8]. The coupling between cAMP abundance and PKA signaling is critical for modulating the events of neurotransmitter vesicles, as well as synaptic transmission and plasticity characteristics. Pharmacological disturbance of GC or PKG reduces the recycling rate and endocytosis of synaptic vesicles. In addition, the NO/cGMP/PKG pathway can adjust the neurotransmitter release and long-term changes of synaptic activity in different brain regions. In summary, the balance between cAMP and cGMP levels is vital for formation of neuronal circuits [7]. PDE inhibitors regulate signaling pathways by enhancing cAMP and/or cGMP levels, which may ultimately promote gene transcription by activating cAMP response element binding protein (CREB) [[9], [10], [11]]. Phosphorylated CREB is an activator that initiates transcription of specific genes coding for neurotransmitter receptors or growth factors such as brain-derived neurotrophic factor (BDNF) [12]. BDNF is one of the target genes of these two pathways. BDNF protein is associated with the generation of synaptogenesis and the proliferation, survival and differentiation of new neurons [13]. BDNF is generated and packaged in vesicles [14]. After secretion, BDNF is highly bound to the tropomyosin-related kinase B (TrkB) receptor, which provides a key molecular mechanism of enhancing neuronal communication, specifically in active neurons of the brain, ultimately leading to increased synaptogenesis and neurogenesis [13]. CREB-dependent gene expression contributes to the production of stable synaptic response and underlies long-term memory formation and sustained long-term potentiation (LTP), which are markers of synaptic plasticity (Fig. 1) [15,16]. Hence, by regulating the cAMP/PKA/CREB or cGMP/PKG/CREB signaling pathway, PDE inhibitors can restore cognitive impairment and improve the symptoms of neurodegenerative diseases by restoring remyelination and neuronal plasticity, reducing apoptosis and increasing neuronal survival, as well as improving motor and cognitive deficits [17,18].

In addition to the neuroplasticity benefits, PDE inhibitors can also play a neuroprotective role [19]. Cyclic nucleotides can reduce the release of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), NF-κB, etc. [20] The interaction between BDNF and TrkB contributes to the activation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase/Akt (PI3K/Akt) cascades, positively affecting neuronal proliferation or survival by activating anti-apoptotic factors and inactivating pro-apoptotic factors [21,22]. BDNF-CREB plays an important role in the survivability and regeneration mature neuron by enhancing release of neurotrophins.