European Journal of Pharmacology 758 (2015) 82–88

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European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar

Neuropharmacology and analgesia

The therapeutic potential of berberine against the altered intrinsic properties of the CA1 neurons induced by Aβ neurotoxicity Masoud Haghani a,b,1,2, Mohammad Shabani c,n,3,4, Mahdi Tondar d,5,6 a

Histomorphometry and Stereology Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran Department of Physiology, Shiraz University of Medical Sciences, Shiraz, Iran c Department of Neuroscience, Kerman Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, 76198 13159 Kerman, Iran d Department of Biochemistry and Molecular & Cellular Biology, School of Medicine, Georgetown University, Washington, DC, United States b

art ic l e i nf o

a b s t r a c t

Article history: Received 12 December 2014 Received in revised form 5 March 2015 Accepted 12 March 2015 Available online 8 April 2015

It was demonstrated that treatment with beta amyloid (Aβ) led to extreme alterations in the intrinsic electrophysiological properties of CA1 pyramidal neurons. Also, malfunction of the cholinergic system is correlated to the memory and cognitive impairments. Several new studies have suggested that Berberis vulgaris can act as a cholinesterase inhibitor. The present study aimed to investigate the effects of berberine (BER) on the Aβ-induced impairments in learning and memory. The male Wistar rats were divided into 4 groups of Sham, BER, Aβ and Aβ þBER. The administration of BER or its vehicle started immediately after the injection of Aβ and followed by 13 days. Then, the animals were tested for learning and memory performance using the Morris water maze (MWM) and passive avoidance tests. Then, they were sacrificed for the whole cell patch clamp recording. The results of the MWM and passive avoidance tasks indicated that administration of the BER in the Aβ þ BER group prevented the memory impairment induced by Aβ. The results of the whole cell patch clamp also showed that administration of the BER restored the Aβ-induced impairments in the firing frequency, half-width and rebound action potential. These results suggested that administration of the BER could ameliorate neurotoxicity induced by Aβ. However, this neuroprotection impact could be resulted from the balance effect of the Ca2 þ entry. The optimal level of Ca2 þ entry by BER could be a major factor that modified the function of the Ca2 þ activated K þ channels and decreased the half-width in the Aβ treated rats. & 2015 Elsevier B.V. All rights reserved.

Keywords: Alzheimer's disease Berberine Neural excitability Learning and memory Amyloid beta

1. Introduction Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder characterized by the impairments of cognition and

n Corresponding author. Tel.: þ 98 34 3226 4196; fax: þ98 34 3226 4198; Mobile: þ 98 913 397 811. E-mail addresses: [email protected] (M. Haghani), [email protected], [email protected] (M. Shabani), [email protected] (M. Tondar). 1 Contribution: This author helped conduct the study and write the manuscript. 2 Attestation: He has seen the original study data, reviewed the analysis of the data, and approved the final manuscript. 3 Contribution: He was responsible for study design, data analysis, and manuscript preparation. 4 Attestation: He is the archival author and attests to the integrity of the original data and the analysis reported in this manuscript. He also attests to approving the final manuscript. 5 Contribution: He contributed in data analysis and manuscript preparation. 6 Attestation: He attests to approving the final manuscript.

http://dx.doi.org/10.1016/j.ejphar.2015.03.016 0014-2999/& 2015 Elsevier B.V. All rights reserved.

memory (Molsa et al., 1995; Tabert et al., 2005). Although causes of AD are still unknown, incidence of this disease is associated with deposition of the amyloid plaques and tangles in the brain (Carter and Lippa, 2001; Kim et al., 2014). The hippocampus plays an important role in the formation of memory. The impairment of memory induced by Aβ could result from abnormal firing and electrophysiological properties of the hippocampal CA1 neurons (Haghani et al., 2012a; Wang et al., 2004). Several studies have indicated that synaptic and cellular changes resulted from the accumulation of Aβ impaired the synaptic plasticity and memory formation (Kim et al., 2014; Walsh et al., 2014). The cholinergic synapses can be negatively affected by the accumulation of Aβ. This phenomenon can lead to degeneration of the cholinergic neurons and loss of cholinergic transmission in AD (Mohammadi et al., 2011). It is a commonly accepted fact that dysfunction of the cholinergic system has a strong correlation with the impairment of cognition and memory. Hence, the inhibition of acetyl cholinesterase (AChE) could preserve and increase the levels of acetylcholine (Ach) in the neuronal synapses, leading to a positive effect on the

M. Haghani et al. / European Journal of Pharmacology 758 (2015) 82–88

AD patients (Kopelman, 1986; Yanez and Vina, 2013). Thus, it is important to find new cholinergic pharmacotherapies for the treatment of AD. Berberis vulgaris is a member of the Berberidaceae family that grows in Asia and Europe. This plant is widely used in traditional medicine. The possible roles of the berberine (BER) as an antipruritic, antiemetic (Aynehchi, 1986; Zargari, 1983), anti-inflammatory, antinociceptive (Kupeli et al., 2002) and antihistaminic (Shamsa et al., 1999) have been reported by several studies. In 2010, Kolar et al. suggested a cholinesterase inhibitory function for the B. vulgaris. Therefore, this plant may have potential therapeutic effects on AD and some AD-related pathological conditions (Kolář et al., 2010). In 2012, Ji and Shen also suggested that BER can interact with four key enzymes, AChE, butyrylcholinesterase (BChE), and monoamine oxidase (MAO) (Ji and Shen, 2012). Several studies have indicated that these enzymes are important role players in the pathogenesis of AD and BER has an inhibitory effect on these enzymes (Huang et al., 2010a, 2010b; Kong et al., 2001). Numerous empirical studies have reported that BER may have considerable neuroprotective impacts on the ischemic brain injury (Simões Pires et al., 2014; Yoo et al., 2006; Zhang et al., 2012; Zhou et al., 2008) and hypoxia (Ye et al., 2009). Moreover, the morphology of the hippocampal neurons was also protected by the BER after the ischemic reperfusion (Yoo et al., 2008). To date, there has not been any report about the effect of BER on the memory and electrophysiological properties of neurons in AD. Therefore, the present study aimed to investigate the effects of BER on the Aβ-induced impairments in learning, memory. To answer this question, this study examined whether or not the administration of BER can prevent the Aβ-induced alterations in the neuronal intrinsic properties.

2. Materials and methods 2.1. Experimental procedures In this study, male Wistar rats (200–250 g) aging 60–65 days were housed 3 per cage, and food and water were available ad libitum. The animals were maintained in a 12-h light–dark cycle. All procedures were conducted in accordance with the animal care guideline approved by the Institutional Ethic Committee (IEC) at the Kerman University of Medical Sciences (Kerman, Iran).

2.2. Surgery The rats were anaesthetized with an intraperitoneal (i.p.) injection of the ketamine (80 mg/kg) and xylazine (20 mg/kg). Then, the animals were fixed in a stereotaxic frame. The rats were given a bilateral injection of the Aβ1-42 (3 μl/side, Sigma) at the concentration of 10 ng/μl into the prefrontal cortex (3.2 mm AP, 2 mm L and 3 mm D) according to the previous studies (Haghani et al., 2012a; Wang et al., 2004). The animals were divided into 4 groups (n ¼8 rats in each group), including the Sham, BER, Aβ and Aβ þBER. The administration of BER (intra-peritoneal) and its vehicle (normal saline) started immediately after the injection of Aβ in Aβ þBER and Aβ groups, respectively. The injection of BER (50 mg/Kg) in the BER-treated animals and the injection of the BER's vehicle (normal saline) in the Sham and Aβ groups were performed daily for 13 days. The Sham group underwent exactly the same surgical procedure that the experimental groups had. An equivalent volume (50 mg/Kg) of the normal saline was injected to the rats as a vehicle of Aβ.

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2.3. Behavioral study The learning and memory of the animals were investigated by the passive avoidance and Morris Water Maze tests. The behavioral tests were performed on the separate rats. 2.3.1. Passive avoidance test A shuttle box apparatus was used for the passive avoidance learning test. This box consisted of a light and a dark chamber. The two chambers were separated by a sliding guillotine door. The passive avoidance test was performed according to two published studies (Aghaei et al., 2014; Haghani et al., 2012b). For the learning trial on day 11 postsurgery, each rat was placed in the light chamber and then the door was opened. When the rat entered to dark chamber, it was exposed to an electrical shock (0.5 mA, 50 Hz, 2 s once). The learning trial was repeated each 5 min until the rats did not enter the dark chamber. The retention trial was performed one day after the learning trial (12th day). It was similar to the learning trial, but it did not have any kind of shock. The delay of entering to the dark chamber was recorded as the step-through latency (STL). The maximum cutoff time for the stepthrough latency was 300 s. 2.3.2. Morris water maze The testing procedure was the same as the process that was described by Shabani et al. (2012). The experimental apparatus consisted of a circular pool filled with water [140 cm wide and 45 cm high]. A platform [15 cm wide and 35 cm high] was placed either 1.5 cm above (visible) or 1.5 cm below (submerged) the water surface. The rats were first trained using the visible escape platform. The water temperature was 21–23 1C. Data were automatically collected by a video image motion analyzer [Ethovision, Noldus Information Technology; the Netherlands]. In a single training protocol, rats were trained with the three blocks of the four trials. The time of each block was followed by a 30 min resting time. All of the experimental groups were tested during the lights on period between 8:00 a.m. and 12:00 p.m. During each trial, the animal was randomly released into the water against the maze wall from one of the four quadrants. For the acquisition, the location of the platform remained constant and rats were allowed to swim for 60 s to find the hidden platform. The latency and distance traveled to find the hidden platform were collected and analyzed later. Memory retention was evaluated during a probe test that was given 2 h after the last training trial. In this trial the platform was removed and the rat was allowed to swim for 60 s. The time and distance spent in the target quadrant [quadrant 4] were analyzed as measures of the spatial memory retention (Shabani et al., 2012). 2.4. Whole-cell patch clamp recording On day 13 postsurgery, animals were anesthetized with ether. Then, the animals were sacrificed quickly by decapitation. Their brains were removed and placed immediately on an oxygenated ice-cold artificial-spinal fluid (ACSF) containing 206 mM sucrose, 2.8 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 2 mM MgSO4, 1.25 mM NaH2PO4, 26 mM NaHCO3, 10 mM D-glucose at pH 7.4 (with 95% O2 and 5% CO2) and adjusted to 295 mOsm. The hippocampus tissues were dissected out on ice. Then, these tissues were fixed in a vibrating microtome chamber (752 M, Campden Instruments Ltd., UK) to obtain the transverse slices (300 mm). Next, the slices were transferred into an incubating chamber (124 mM NaCl, 2.8 mM KCl, 2 mM CaCl2, 2 mM MgSO4, 1.25 mM NaH2PO4, 26 mM NaHCO3, 10 mM D-glucose, pH 7.4, 295 mOsm) for 60 min at 35 1C. Then, the slices were maintained at room temperature (22–24 1C).

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The whole cell recordings were performed according to the method of Haghani et al. (Haghani et al., 2012a, 2013). The slices were transferred to a submerged recording chamber mounted on the stage of an upright microscope (Olympus; BX 51WI) with the continuous flow of an ice-cold artificial cerebrospinal fluid (ACSF). The CA1 pyramidal neurons were observed with a 60  water immersion objective lens using the Nomarski-type differential interference contrast imaging with an infrared illumination. Images were taken using a CCD camera (Hmamatsu, ORSA; Japan). The patch pipettes (3–7 MΩ) were pulled by a vertical puller (PC10; Narishige, Tokyo, Japan). These pipettes were filled with an internal solution that had 135 mM potassium methylsulfate (KMeSO4), 10 mM KCl, 10 mM Hepes, 1 mM MgCl2, 2 mM Na2ATP, and 0.4 mM Na2GTP. The solution's osmolarity and pH were 290 mOsm and 7.3, respectively. Cells were recorded at room temperature (23– 27 1C). Whole cell current clamp recordings were made from the CA1 pyramidal neurons using a Multiclamp 700B amplifiers (Axon Instruments, Foster City, CA) equipped with a Digidata 1320 A/D converter (Axon Instruments, Foster City, CA). The electrophysiological responses were filtered at 5 kHz. Then, they were sampled at 10 kHz and stored for an offline analysis. To investigate the effect of BER on the excitability of neurons, the CA1 pyramidal neurons were elicited by hyperpolarizing currents ranging from  0.1 to 0.5 nA in 0.1 nA increments followed by a fixed depolarizing current with 0.3 nA intensity. The resting membrane potential (RMP), half-width and peak amplitudes, and after hyperpolarization (AHP) action potentials were also measured. The results were expressed as the mean 7S.E.M. One way ANOVA was used for the multiple comparisons followed by Tukey's posthoc test. The repeated measure ANOVA was used to analyze the data of the MWM task. P o0.05 was considered statistically significant.

3. Results 3.1. Behavioral experiment 3.1.1. BER partially improved the STL time of the passive avoidance test following the bilateral injection of Aβ The results of the passive avoidance test (Fig. 1A) indicate that all groups learned the avoidance task with the same number of foot shocks and this experiment did not detect statistical differences in the training trials. However, the STL of the retention trial in the Aβ group (115.7735.01) significantly decreased (Po0.05) compared to the Sham (221.2728.9) and BER groups (269.03731.7). In addition, the administration of BER in the Aβ þBER group only partially prevented the memory impairment induced by beta amyloid. The initial latency of entrance into the dark chamber was increased by BER. This latency was enhanced to its levels in the Sham and BER groups. Although this increase in the STL of the Aβ þBER group remained marginally significant compared to the Aβ group, it was not statistically significant (Fig. 1B). 3.1.2. BER improved the spatial memory impairment induced by the bilateral injection of Aβ The results of the spatial learning and memory from the Morris water maze task showed that the injection of beta amyloid increased the distance (Fig. 2A) and time of the swimming (Fig. 2B) to reach the platform in block 2 (Po0.001) and block 3 (Po0.001) in the Aβ group compared to the Sham and BER groups. In the Aβ þBER group, traveling distance for block 2 (Po0.001) was higher compared to the Sham and BER groups. However, the administration of BER significantly lowered the traveling distance in block 3 in the Aβ þ BER group compared to the Aβ group (Po0.01). Furthermore, the administration of BER also decreased the traveling time in the

Aβ þBER group compared to the Aβ group (Po0.01). The swimming speed was the same for all the groups (Fig. 2C). In the probe trial, the spent percentage in the correct quadrant was significantly decreased (P o0.05) in the Aβ group compared to the Sham and BER groups. However, there was a trend toward an increment in this percentage in the Aβ þBER group (Fig. 2D). Moreover, the percentage of swimming in the right quadrant (P o0.01) also was significantly decreased in the Aβ group compared to other experimental groups. It is notable that the administration of BER prevented this swimming deficit in the Aβ þBER group. Further analysis revealed that the percentage of swimming in the right quadrant did not show a significant difference in the Aβ þBER group compared to the Sham and BER groups (Fig. 2E). In addition, there was no significant difference in the crossing number in the correct quadrant among the groups (Fig. 2F).

3.2. Electrophysiological experiments The whole cell patch clamp's results showed that the mean resting membrane potential and the peak amplitude of action potential were not significantly different in all the groups (Fig. 3A and B). However the CA1 hippocampal pyramidal neurons from the Aβ group showed a significant decrease in the event frequency (Fig. 3C), the administration of berberine could at least partially restore this event (Firing frequency). The result indicated that the firing rate returned to its values in the Sham and BER groups. However, these values did not quite reach a significant difference in the Sham and BER groups compared to the Aβ group (Fig. 3C). The present study showed that the amplitude of AHP in the Aβtreated animals was significantly greater than other groups and the administration of BER failed to recover the AHP amplitude (Fig. 3D). Moreover, the action potential half-width was also significantly extended by the injection of Aβ sin the Aβ þBER group compared to the Sham (P o0.01) and BER (P o0.05) groups (Fig. 3E). By contrast, the administration of BER caused apparent spike broadening in the BER group compared to the Sham group. However, BER almost prevented the broadening of action potential induced by Aβ. As a result, the average half-maximum width of action potential in the Aβ þ BER group was significantly (P o0.05) lowered compared to the Aβ group. It is also notable that the administration of BER alone increased (P o0.05) the halfmaximum width of action potential compared to the Sham group (Fig. 3E). A significant decrease in the event frequency combined with an irregularity of firing (coefficient of variance) was detected. These changes were shown by C.V. in Fig. 3F. Although the administration of berberine partially restored the firing frequency, it did not affect the regularity of firing. Fig. 4 that represents the spontaneous sample traces shows the Aβ-induced irregular firing on the spike discharge regularity of CA1 neurons. Conventional whole cell current clamp recording from a CA1 neuron displays a regular firing in control conditions. The half-widths of action potentials were larger in the Aβ and Aβ þ BER-treated groups than those in the Sham and BER groups. In another set of experiments, we used hyperpolarizing currents steps that followed a fixed depolarizing current with 0.3 nA intensity. Under these conditions, another interesting finding was that the number of rebound action potentials after preconditioning by hyperpolarizing currents was significantly lowered for all the steps in the Aβ group compared to the BER group (Fig. 5). With increasing the hyperpolarizing currents intensity, the number of rebounded pulse gradually increased in all groups, including the Aβ. However, this group had a lower pulse-increase at the  0.5 nA current compared to other groups. Moreover, the administration of BER almost prevented this effect of beta amyloid on the number of rebounded pulse.

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Fig. 1. Neuroprotective effect of BER on the passive avoidance task. All groups learned the avoidance task with the same number of foot shocks. There was not any difference in the training trial (A). The administration of BER prevented the memory impairment induced by Aβ (B). The values are shown as meanþ S.E.M. Significant differences between the Aβ group versus Sham (*Po 0.05) and BER (#P o 0.05) groups were detected.

Fig. 2. Neuroprotective effect of BER administration on the Aβ-induced spatial memory impairment in the MWM task. Distance-moved (A) escape latency (B) and swimming speed (C) of the animals during training trial. The traveling percentage in correct quadrant (D), the swimming percentage in correct quadrant (E) and the crossing number of the animals in the probe trial (F). The values are shown as mean þS.E.M. Significant differences between the Aβ group versus Sham (*P o0.05, **P o 0.01 and ***P o 0.001), BER (#Po 0.05, ##Po 0.01 and ###Po 0.001) and Aβþ BER groups (xP o 0.05 and xxPo 0.01) were detected.

4. Discussion In this study, a rat model of Alzheimer's disease was created by bilateral injection of Aβ in the prefrontal cortex to investigate the neuroprotective effects of BER as a cholinesterase inhibitory

molecule. We found that the administration of BER prevented the impairing impacts of Aβ on the learning, memory and electrophysiological properties of the CA1 pyramidal neurons. There are multiple mechanisms involved in the pathogenesis of AD, including Aβ deposition, tau phosphorylation, abnormal

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Fig. 3. The adverse effect of Aβ on the electrophysiological properties of CA1 pyramidal neurons and the neuroprotective effect of BER against the alterations induced by Aβ treatment. Electrophysiological properties, including resting membrane potential (A), peak amplitude of action potential (B), event frequency (C), AHP amplitude (D), halfwidth (E) and coefficient variation (F), were recorded in the whole cell patch. The values are shown as mean þS.E.M. Significant differences between the Aβ group versus Sham (*P o0.05 and **Po 0.01), BER (#Po 0.05 and ##P o0.01) and Aβþ BER groups (xPo 0.05 and xxP o 0.01) were detected.

Fig. 4. Representative spontaneous sample traces recorded from different groups in the whole cell patch clamp mode.

neuroinflammatory response and cholinergic dysfunction. Acetylcholine is a part of cholinergic system that plays crucial roles in the memory and learning processes. Thus, a possible cause for the memory impairment in AD might be decreases in the function of cholinergic system, contributing in the loss of memory in AD patients. The cholinergic theory is based on the assumption that AD can be caused following the alternations in the levels of acetylcholine in the brain. Several studies have demonstrated a

significant loss of cholinergic neurons in the brains of AD patients (Parikh et al., 2014; Yan and Feng, 2004). In the present study, the bilateral injection of Aβ was mostly associated with a significant memory deficit that was revealed by the passive avoidance and MWM tasks. These data were consistent with the previous studies indicating that the bilateral Aβ injection in the prefrontal cortex caused a memory deficit (Haghani et al., 2012a; Wang et al., 2004). However, treatment by BER for 12 days significantly improved the

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Fig. 5. BER administration recovered rebound action potential decrement induced by Aβ injection. The number of rebound action potentials evoked by hyperpolarizing currents (  100 to  500 pA) that were followed by fixed depolarizing currents with 300 pA intensity (right linear graph) and sample traces evoked for each group by  100 and  500 pA hyperpolarizing currents. The values are shown as mean þ S.E.M. Significant differences between the Aβ group versus Sham (*P o 0.05, **P o 0.01), BER (#P o0.05, ##P o0.01 and ###Po 0.001) and Aβ þ BER groups (xPo 0.05) were detected.

memory performance in both passive avoidance and MWM tasks. The improvement of memory in BER-treated animal is consistent with previous studies (Kalalian-Moghaddam et al., 2013; Moghaddam et al., 2013). To understand the positive functional impacts of BER on the memory impairment, this study explored the electrophysiological effects of BER on the CA1 pyramidal neurons in a rat model of AD. It was demonstrated that the in vivo treatment with Aβ led to extreme alterations in the intrinsic electrophysiological properties of the CA1 pyramidal neurons and these changes were associated with a behavioral deficit in AD (Wang et al., 2004). In this study, we also found that the bilateral injection of Aβ caused a significant increase in the AHP amplitude and half-width (Wang et al., 2004). In the hippocampal pyramidal neurons, the BK channels are responsible for the AHP amplitude and spike repolarization (Storm, 1987). Several studies have suggested that Aβ impaired the calcium homeostasis (Kawahara et al., 1997; Smith et al., 2005). The increase in the Ca2þ currents is induced by Aβ influenced K þ current from the BK channels. It is possible that a chronic loss of K þ reduced the neural excitability (Furukawa et al., 1996). This result was in line with our findings that Aβ decreased the neuronal excitability by enlargement of AHP amplitude. Although treatment with BER in the Aβ-treated rats did not have any effect on the AHP amplitude, it significantly reduced the half-width. What is surprising is that the administration of BER significantly increased the

half-width in the normal animals that received BER (BER group). This unexpected finding suggests that BER may directly increase the Ca2þ entry. However the normal and healthy neurons have a balance for the Ca2 þ entry, in pathological conditions, such as ageing, trauma and neurodegenerative disorders, this balance could be disrupted, leading to cellular damages. Therefore, a delicate control for the Ca2þ levels is important for neuronal health (Uteshev, 2012). Moreover, several studies have suggested that the elevated levels of cytosolic Ca2 þ have been linked to AD. Conversely, neuroprotective effects of the moderate elevations in cytosolic Ca2þ by continued activation of α7 nicotinic acetylcholine receptors (nAChRs) have previously well documented (Akaike et al., 1994; Egea et al., 2007). BER is well known as a cholinesterase inhibitory factor (Kolář et al., 2010). This plant may cause a persistent activation of nAChRs, leading to an optimal level of Ca2 þ entry. It is therefore likely that such connections may exist between the elevated half-width and the continued activation of nAChRs by BER in the BER group. Hence, it could conceivably be hypothesized that the optimal Ca2þ entry significantly decreased the half-width in the Aβ þBER group. However, the time of the half-width was higher compared to the normal animals. We previously showed that the Aβ treatment induced a strong inward Ca2 þ current (Wang et al., 2004), which might be partially optimized by BER. Therefore, the administration of BER following the injection of Aβ recovered the halfwidth only to a limited degree.

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The ability of Aβ to modulate excitability and regularity of firing is consistent with our previous work (Haghani et al., 2012a). The result of this study showed that under the whole cell current clamp conditions, the administration of BER caused a significant increase in the number of rebound action potentials for all of the hyperpolarizing currents (  0.1 to  0.5 nA) compared to the Aβtreated animals. Wang et al. (2004) suggested that BER blocked the transient outward potassium current (IA) in the CA1 pyramidal neurons. The findings of the current study are consistent with those of Wang et al. It is a known fact that IA regulates the actionpotential frequency as well as the rebound activity. Therefore, the administration of BER probably recovered the effects of beta amyloid on the IA current. This is a possible explanation for the improvement of event frequency and excitability of the CA1 pyramidal neurons. In conclusion, the results of this study altogether suggest that administration of BER ameliorates neurotoxicity induced by Aβ. However, this neuroprotection may be a result of balanced effect of Ca2 þ entry via persistent activation of nAChRs. Therefore, this could be a major factor that modifies the Ca2 þ -activated K þ channel function. Moreover, another candidate that could be modulated by BER treatment is IA current, which provide a possible explanation for improvement of the excitability. Thus, it is therefore likely that this connection exists between BER and improvement of excitability. Therefore, further research is clearly required to shed light on the molecular mechanisms underlying the impacts of BER on Ca2 þ currents, Ca2 þ -activated K þ channels and IA current in Alzheimer disease. Conflict of interest The authors declare no conflict of interest.

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The therapeutic potential of berberine against the altered intrinsic properties of the CA1 neurons induced by Aβ neurotoxicity.

It was demonstrated that treatment with beta amyloid (Aβ) led to extreme alterations in the intrinsic electrophysiological properties of CA1 pyramidal...
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