Neuroprotective effects of vinpocetine, as a phosphodiesterase 1 inhibitor, on long-term potentiation in a rat model of Alzheimer's disease

Abstract

Background: Vinpocetine (Vin) is known as a phosphodiesterase 1 inhibitor (PDE1-I) drug with multilateral effects, including antioxidant and anti-inflammatory activity. In this research, we investigated the neuroprotective and therapeutic effects of Vin through hippocampal synaptic plasticity on a rat's model of Alzheimer's disease (AD) induced by an intracerebroventricular (ICV) injection of beta-amyloid (Aβ).

Methods: Sixty adult male Wistar rats were randomly divided into six groups: 1. control, 2. sham, 3. Aβ, 4. pretreatment (Vin + Aβ): Vin (4 mg/kg, gavage) for 30 days and then, inducing an AD model by an ICV injection of Aβ(1-42), 5. treatment (Aβ + Vin): inducing an AD model and then receiving Vin for 30 days by gavage, and 7. pretreatment + treatment (Vin + Aβ + Vin): receiving Vin by gavage for 30 days before and 30 days after the induction of an AD model. After these procedures, via stereotaxic surgery, the stimulating electrodes were placed at the perforant pathway (PP) and the recording electrodes were implanted in the dentate gyrus.

Results: Excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude in the Aβ group meaningfully diminished compared to the control group after the induction of long-term potentiation (LTP).

Conclusions: Vin could significantly prevent the Aβ effects on LTP. It can be concluded that pretreatment and treatment with Vin can be neuroprotective against harmful consequences of Aβ on hippocampal synaptic plasticity.

Keywords: Alzheimer’s disease; Beta-amyloid; Hippocampus; Long-term potentiation; Phosphodiesterase1 inhibitor; Vinpocetine.

Fig. 1

The experimental timeline. To create a rat model of Alzheimer’s disease, the rats were anesthetized with xylazine (10 mg/kg) and ketamine (100 mg/kg) 30 days after vinpocetine administration (Vin pretreatment, 4 mg/kg) in experimental groups and transferred to a stereotaxic device. The intraventricular injection of amyloid-beta (Aβ) solution (2 μL) was done at a rate of 1 μL/2 min. Following recovery, vinpocetine was re-administered through oral gavage once a day for 30 days (Vin treatment). Vin-treated rats were divided into three groups: 1. pretreatment.2. treatment. 3. pretreatment + /treatment. After treatments, in vivo electrophysiological recordings were done for the determination of the excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude in the dentate gyrus of the hippocampus. LTP was induced through a high-frequency stimulation of the perforant pathway. For the histological study, the animals were perfused with formol-saline

Fig. 2

Schematic drawing of a rat brain coronal section from Paxinos and Watson, showing the trace of recording electrodes (arrow) in the dentate gyrus (DG) (A). The cross-section view of the hippocampal area with the tip of recording electrodes (arrowhead) in DG; sample on left and atlas plate on right (B). Scale bar: 1 mm

Fig. 3

Population spike (PS) amplitude and field excitatory postsynaptic potential (fEPSP) slope, assessed in a representative sample field potential in the hippocampus of the control rats (A). Sample traces of evoked field potential were recorded in the dentate gyrus (DG) of the hippocampus before and following high-frequency stimulation (HFS) of the perforant pathway (PP) in all groups (B)

Fig. 4

The effect of pretreatment, treatment, and pretreatment + treatment with Vinpocetine (Vin) on excitatory postsynaptic potential (EPSP) slope in the dentate gyrus (DG) utilizing 400 Hz tetanization of the AD-induced rats. Long-term potentiation (LTP) of the EPSP slope in DG granular cell synapses is meaningfully dissimilar between groups. Values are represented as the mean ± SEM% of the baseline. *: P < 0.05 compared to the control group and $: P < 0.05 compared to the AD group

Fig. 5

Effect of pretreatment, treatment, and pretreatment + treatment with Vinpocetine (Vin) on values of population spike (PS) in the dentate gyrus (DG) utilizing 400 Hz tetanization. Long-term potentiation (LTP) of PS in DG granular cells in the hippocampus is meaningfully dissimilar between groups. Values are represented as the mean ± SEM% of the baseline. *: P < 0.05 compared to the control group; $: P < 0.05, $$: P < 0.01, $$$: P < 0.001, and $$$$: P < 0.0001 compared to the AD group; and ^: P < 0.05 and ^^: P < 0.01 compared to the pretreatment + treatment group