Part1: Genistein: A Potential Natural Lead Molecule For New Drug Design And Development For Treating Memory Impairment

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Abstract: Genistein is a naturally occurring polyphenolic molecule in the isoflavones group which is well known for its neuroprotection. In this review, we summarize the efficacy of genistein in attenuating the effects of memory impairment (MI) in animals. Scopus, PubMed, and Web of Science databases were used to find the relevant articles and discuss the effects of genistein in the brain, including its pharmacokinetics, bioavailability, behavioral effects, and some of the potential mechanisms of action on memory in several animal models. The results of the preclinical studies highly suggested that genistein is highly effective in enhancing the cognitive performance of the MI animal models, specifically in the memory domain, including spatial, recognition, retention, and reference memories, through its ability to reduce oxidative stress and attenuate neuroinflammation. This review also highlighted challenges and opportunities to improve the drug delivery of genistein for treating MI. Along with that, the possible structural modifications and derivatives of genistein to improve its physicochemical and drug-likeness properties are also discussed. The outcomes of the review proved that genistein can enhance cognitive performance and ameliorate MI in different preclinical studies, thus indicating its potential as a natural leader for the design and development of a novel neuroprotective drug.

Keywords: genistein; isoflavone; memory impairment; neuroprotection; phytomedicine

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1. Introduction

Memory is a state of gaining, retaining, and retrieving information which includes all knowledge gained throughout one's experience such as truths that are known, incidents remembered, and abilities nurtured throughout one's life. Two main types of memory are declarative and non-declarative memories, with the former being the daily memories while the latter mainly consist of memories retrieved reflexively[1. Memory disorders, often known as memory impairment (MI), are key indicators for diagnosing certain aetiologies associated with syndromes. Some cases in point include Alzheimer's, Parkinson's, Huntington's, Korsakoff's, and Creutzfeldt-Jakob's diseases (Figure 1)[2-5]. MI mainly affects declarative memory, as is the case with amnesia and dementia, but this is not always the case with the latter, since dementia is defined as the decline in two or more areas of cognition. In other words, dementia is not limited to declarative memory disorder alone since it also affects other parts of memory [1].

Dementia can affect memory in both primary and secondary ways. Primary memory disability may include the decline in declarative memory in which Alzheimer's disease is a good demonstration since declarative memory is one of the areas of cognitive that suffer from the decline. On the other hand, the secondary manner in which memory ability is affected is when there are cognitive deficits that can impede memory performance, e.g., attentional disorder dementia that may hinder multiple aspects of memory performance [1].

Currently, there is no confirmed treatment that can totally attenuate the development of Ml. Nonetheless, memory improvement therapies are important for maintaining a patient's cognitive function with the aim of combating MI risk factors. Estrogen, which is a reproductive hormone, has a broad spectrum of action with its neuroprotective role. Nevertheless, its potential as a neuroprotective agent can be ameliorated by the proliferation and oncogenic effects on certain cells, causing the need for the development of selective estrogen receptor modulators(SERMs), including the naturally occurring phytoestrogens [6]like genistein.

Genistein is an isoflavone (Figure 2) predominantly found in Glycine max(soybean)extract among many other sources, such as legumes, peanuts, and green peas. Genistein is produced following the metabolism of the biologically active glycoside genistin [7]. Since many traditional Asian foods are made from soybean, e.g., natto, tofu, and sufu [8], Asian countries recorded a relatively high amount of genistein (25-30 mg/day)intake when compared with Western countries (2 mg/day). In fact, fermentation of soybeans is also one of the best ways to release genistein other than digestion [9].

The pharmacological properties of genistein revealed that it has the potential to be a lead molecule in the treatment of a wide range of diseases, including postmenopausal symptoms, cancer, bone, brain, and heart problems [l0. Since genistein is believed to pass the blood-brain barrier to exert its neuroprotective effect, it is extensively applied in the investigation of the treatment of neurodegenerative diseases, such as Alzheimer's, Huntington's, and Sanfilippo disease (Figure 3)[11-13]. Recent investigations have focused on its effect on MI where genistein protects against MI by （1） reducing the production of ß-amyloid protein(Aβ), (2)preventing neuro-inflammatory by inhibiting nuclear factor-activated B cells(NF-kB), (3)inhibiting the activity of acetylcholinesterase(AChE), (4) decreasing the hyperphosphorylation of tau protein to prevent neuronal fiber entanglement (NFT), (5)up-regulating the activity of Apolipoprotein E (ApoE) to reduce the deposition of Aβ, and (6) exerting its antioxidant properties and reducing oxidative stress by eliminating reactive oxygen species (ROS) [14-19].

An overview of numerous studies on genistein against MI is offered in this review to better understand the potential functions of genistein in ameliorating MI. The study design of each important work on Ml, in terms of animal models, memory testing methodologies, and its dose, is also summarized. Additionally, an overview of the data gathered on the effectiveness of genistein in the treatment of MI is presented. The potential protective mechanisms imparted by genistein are also highlighted to close the knowledge gap, regarding its use as complementary medicine or an adjuvant for MI. This review also outlines some of the obstacles to and the potential for improving genistein drug delivery for MI treatment. In addition, various structural modifications and derivatives of genistein were discussed in order to increase its safety, efficacy, physicochemical, and drug-likeness properties.

2. Description of Study Design 

2.1.Animals

Rats and mice were used in the majority of investigations. All experimental protocols were authorized by the relevant institution's animal welfare committees and conducted in accordance with the guidelines for the use and care of laboratory animals.

2.2. MI Models

Each included study focused on different types of MI models. For example, Rum-manet al. [19]focused on hypoxia-induced Ml while Luet al. [20]scrutinized chronic sleep deprivation (CSD)-induced memory deficits. Two studies employed a streptozotocin (STZ)-induced model of MI, where Pierzynowska et al. [13] investigated an STZ-induced Alzheimer's disease(AD)model while Rajput et al. [21]focused on STZ-induced diabetes for an MI model. On the other hand, other MI models included scopolamine-induced cognitive impairment, lipopolysaccharide(LPS), lead, kainic acid (KA), aging, and β-amyloid [22-27].

2.3. Genistein DOose

During the course of the treatment, all of the selected investigations used purchased genistein (purity>98%). The majority of the investigations utilized genisteinat0.5-150 mg/kg. The two most common doses chosen in MI in-vivo models were 10 and 20 mg/kg. In terms of route of administration, eight investigations utilized oral (p.o.)genistein, while in two studies it was given intraperitoneally (i.p.). Prior to the behavioral assessments, genistein treatment was performed for a minimum of 4 days and a maximum of 90 days.

2.4. Toxicity Profile of Genistein

In an in vivo study, Ek et al. [28] investigated the toxicity profile and pharmacokinetics of genistein in mice. Female BALB/c mice were used during the studies, in which each mouse received an intraperitoneal injection with 0.2 mL(10%) dimethylsulphoxide/phosphate buffer solution (DMSO/PBS) containing either 0,2,20,200,400 and 800 ug of genistein daily for 10 days. Subsequently, the mice were monitored for 14 days, following which any surviving mice were sacrificed for histology analysis. The findings indicated that the mice treated with genistein did not show any signs of toxicity, nor did they become frail, lethargic, or lose any weight, even following treatment with the highest dose of genistein (40 mg/kg). Further, genistein was well tolerated in the in vivo subchronic and chronic safety investigations at doses up to 500 mg/kg/day administered orally for up to 52 weeks according to Nasri and Pohjanvirta [29].

2.5. Memory Testing Procedure

Levin and Buccafusco [30]stated that there are three main major cognitive dysfunctions in animal model studies, namely (1) pharmacological models, (2) toxicological models, and (3) genetically modified models. Neural bases of learning, memory, and attention were determined by using critically significant animal models of cognitive impairment. Pharmacological models are the most widely used in cognitive disorders studies since they provide the basis for understanding the role of the neurotransmitter-receptor system involved in cognitive processes, such as learning, memory, and attention [30].

"The cholinergic system (muscarinic and nicotinic) and glutamate receptors, mostly the N-methyl-D-aspartate (NMDA)receptors play critical neuronal roles in the cognitive functions. Acetylcholine is synthesized from the dietary choline and acetyl coenzyme A via the enzyme choline acetyltransferase (CAT). The metabolism of acetylcholine occurs in the neuronal synapse, facilitated by the enzyme acetylcholinesterase. To date, some cholinesterase inhibitors have been developed to ameliorate impaired memory, such as donepezil, rivastigmine, and galantamine [31].

To induce memory impairment in cholinergic system animal models, antimuscarinic agents, including scopolamine, atropine, pirenzepine, trihexyphenidyl, benztropine, biperiden, and dicyclomine [32], have been utilized. Nicotinic receptor antagonists, such as mecamylamine (a non-competitive nonselective nicotinic receptor antagonist), chlorison diamine and d-tubocurarine (non-specific nicotinic antagonists), dihydro-β-erythroidine hydrobromide (DhβE; a specific receptor α4β2 antagonist), and methyl aconitine (MLA)(specific receptor α7 antagonist), have all been utilized to stimulate cognitive defects in animal models [33]. Similarly, NMDA receptors also play a critical role in cognitive functions, since their activation is associated with long-term potentiation (LTP) to strengthen the signal transmission between neurons. Therefore, to stimulate cognitive impairment in animal models through the glutamate-receptor system, many researchers have opted for the use of NMDA receptor antagonists, such as MK-801, ketamine, and phencyclidine (PCP)[34].

Neurological toxicology has been successfully applied in the investigation of cognitive dysfunction in animal models. Neurotoxicity in animal models is achieved by using neurotoxicants, such as lead, mercury, and polychlorinated biphenyls (PCBs) since the cognitive defects have been well-modeled in monkeys and rodents models [30]. Lead, in particular, has been reported in many studies to induce oxidative stress. It induces oxidative stress by increasing vulnerability towards reactive oxygen species (ROS) and reducing antioxidants such as catalase (CAT) and superoxide dismutase (SOD). ROS are mostly generated by protein kinase C(PKC) and nuclear factor-activated B cells (NF-kB), which can be induced by lead exposure. Lead can also cause neuronal cell apoptosis by mimicking calcium ions and binding to the voltage-gated calcium ion channels, thus affecting the neurotransmitter balance in the hippocampus which can cause apoptosis and autophagy. Finally, lead can also induce neuroinflammatory reactions by activating NF-kB [24].

Streptozotocin (STZ) is widely used in the induction of diabetes in animal models of Alzheimer's disease(AD). Intracerebroventricular injection of STZ induces hyperphosphorylation of tau protein and accumulation of β-amyloid which can lead to MI [13].STZ is also used to induce a diabetic state in animal models to stimulate MI by causing hyperglycemia and hypoinsulinemia. Consistently high blood glucose induces inflammation and oxidative stress, as well as activating multiple downstream kinases that activate the release of pro-inflammatory cytokines, such as IL-6, IL-1β, and TNF-α, further damaging neurons (Figure 4). Although STZ can cause significant weight loss in animal models, aligned with a major symptom of hyperglycemia, treatment with antihyperglycemics and insulin sensitizers can ameliorate the cognitive deficits [35].

Genetically modified animal models are increasingly used in cognitive impairment studies since they can mimic certain defects, including Alzheimer's disease(AD),β-amyloid deposition, amyloid precursor protein (APP), and cholinergic-receptor knockout, to be employed for new drug development [30]. On the other hand, memory is accessed using different experimental procedures, including(1)Morris water maze (MWM), (2) passive avoidance test (PAT),(3) novel object recognition (NOR),(4) object location recognition (OLR), (5)novel object discrimination (NOD), (6) elevated plus maze(EPM), (7) delayed spatial alternation (DSA), (8) differential reinforcement of low rates of responding (DRL), (9)Radial arm maze (RAM) task, and (10)Y-maze. Among these studies, MWM, NOR, and OLR are the three most commonly used methods for memory testing.

2.5.1.Morris Water Maze (MWM)

The Morris water maze (MWM) is a circular, water-containing steel pool with differing diameters and heights, ranging from 100-160 cm in diameter and 38-80 cm in height. The pool is divided into four similar quadrants(marked as NE, SE, NW, and SW) and a platform will be submerged underwater in the middle of one of the stated quadrants [19,22]. The platform is kept at the same place throughout the testing session.

The animals are trained for a few days to determine the location of the platform During training, they are released from different quadrants while facing the quadrants will and will swim towards the submerged platform for 60,90, or 120 s. If the animals fail to find the platform during the allocated time, they will be placed onto the platform for another 10 or 30 s to make them feel familiar. The training phase will continue for a few days before the actual trial where a harmless opaque ink will be put inside the pool to hide the location of the platform [22]. The animals will be given a certain time to determine the location of the submerged hidden platform. The time taken will be recorded to assess the long-term spatial memory. Another assessment can also be performed to evaluate memory retention, in which during the trial phase, the platform will be removed and the number of animal crossing on the target platform's former location will be recorded using a video camera [24].

2.5.2.Passive Avoidance Task (PAT)

The passive avoidance task(PAT) involves the use of an apparatus that is divided into illuminated and dark compartments that are connected by a small gate. During the acclimatization phase, the animals are placed inside the apparatus for 15 min to familiarize themselves with the new environment. During the training trial, the animals will be put inside a dark compartment, and a small electric shock (39 V for 3s or 1 mA for 1 s)will be released to their feet. After 24 h of the training trial, the actual test will be performed during which each animal will be placed in the illuminated compartment. The latency period before it entered the dark compartment will be recorded up to a maximum of 300 s to assess the animal retention memory of the electric shock in avoiding the dark compartment when they received the shock [19,27].

2.5.3. Novel Object Recognition (NOR)

The novel object recognition test (NOR)is performed to assess the animal's recognition memory. The test is performed in a rectangular box(40 cm × 50 cm ×50 cm) that is painted in black with a video camera set up above the chamber to record the animal's behavior. In the habituation phase, the animals are placed inside the chamber without the presence of any objects for at least 10 min for three consecutive days. During the trial phase, the animals will be allowed to roam inside the box containing two identical objects (typically plastic balls) for 5 min. After 30 min, the test trial will be performed where one of the objects will be replaced with another object of a different color. The exploratory behavior of the animals will be observed based on the sniffing or touching action of the object, The duration of contact with each of the objects will be recorded to evaluate the recognition memory [19,20].

2.5.4.Object Location Recognition (OLR)

The object location recognition test is used to assess the recognition memory, which is similar to the NOR test. The apparatus is a rectangular box(40× 50× 50 cm)with a dark painted chamber inside and a video camera mounted on top of the chamber to observe the animals' exploratory behavior. The objects used are two small plastic bottles, identical in size and shape but different in color. The method is divided into three phases: habituation, familiarization, and test phases [20].

Habituation phase: The animals are allowed to roam freely inside the chamber with no objects for 10 min for three consecutive days.

Familiarization phase: On the fourth day, the animals are placed inside the chamber containing two identical objects for 5 min.

Test phase: 30 min after the familiarization phase ended, the animals will be placed inside the chamber again, but one of the original objects will be replaced with a different object while the remaining original object is still kept inside the chamber.

To avoid any possible odor cues, the objects and the floor of the chamber are cleaned using 70% ethanol at the end of each trial session. The animals' exploratory behavior during the test phase is observed based on the sniffing or touching action of the object using the animals' noses [22].

2.5.5. Novel Object Discrimination (NOD)

The novel object discrimination test allows the animals to explore two objects for 5min during the familiarization phase. After 4 h, one of the objects will be replaced with a new one. Subsequently, the exploratory behavior of the animals, such as chewing, licking, sniffing, or touching the object with their noses [23], will be recorded.

2.5.6. Elevated Plus Maze (EPM)

The elevated plus-maze involves the use of an elevated plus-shaped apparatus which consists of four elongated rails(arms), two of which are open arms and the other two, enclosed arms. The two open arms are situated across each other, perpendicular to the enclosed arms with a platform in the middle [36]. During the training phase, the animals are placed at the end of the open arm, facing away from the central platform for three days. The transfer latency time (TLT)is recorded as the time taken by the animals to enter the enclosed arm from the starting point on the open arm within the 90s. On the fourth day, during the test trial, the TLT is recorded 24 h after the global cerebral ischemia-reperfusion (IR)brain damage, which is the index for memory [21].

2.5.7.Delayed Spatial Alternation (DSA)/Differential Reinforcement of Low Rates of Responding (DRL)

The delayed spatial alternation (DSA)and differential reinforcement of low rates of responding(DRL) involve the use of similar apparatus, a Skinner box, containing two retractable levers between pellet dispensers with a pair of cue lights directly above each lever. During the training phase, the animals are trained to press the lever based on the cue light for food pellets as a reinforcer, based on an autoshaping program. To prevent the animals from developing a side bias towards the lever, the lever associated with the reinforcement is interspersed with every five reinforcers delivered. The DSA task involved a delay in the lever press for 0,3,6,9 or 18s. The slow responding criteria are divided into six main training sessions, the first two sessions entailing a fixed-ratio 1 schedule for 200 trials or 90 min. The third and fourth sessions are composed of a DRL-5s schedule, while reinforcement is dependent on a 5s delay between responses. The same is applied to the last two main sessions with DRL-10 s schedule that requires a 10s delay between responses. The animals are tested on the DRL-15s schedule for at least 30 sessions [26].

2.5.8.RAM Task

The radial arm maze(RAM) task is employed to assess the spatial memory and involves the use of an elevated eight-armed radial maze with each arm extended from the octagonal central platform. At the end of each arm, a food container is available for the experimenter to deposit food for reinforcement. Nevertheless, during the trial phase, only some of the arms will contain food pellets in the food container.

During the training phase, the animals will be placed at the central platform and will be allowed to freely explore the maze to acquire food pellets. During the process, the animals will learn not to re-enter the arms that they have visited in the same trial in the absence of food. In the test trial,10min will be given for the animals to explore the maze and to consume all the pellets placed in some of the arms. The correct and incorrect choices are used to evaluate each of the animals' performances. Should the animals re-enter the arms without food that they have visited, it will be considered as an error [27].

2.5.9.Y-Maze

The Y-maze test is used by Bagheri et al.[27] and Shahmohammadi et al.[23] to assess the spatial recognition memory of the animals. The apparatus used is a three-armed maze, where each arm is 120°from another and resembles the shape of a capital"Y". Each of the arms is connected by an interconnecting part. The protocol was conducted to evaluate spatial learning using the spontaneous alternation in which the animals are naive to the nature of the maze. The animals are placed at the end of one arm and will be allowed to move freely in an 8 min session. Alternations are observed as successful entries into each of the three arms on overlapping triplet sets, each one with non-repetitive arms. The alternations percentage is subsequently calculated as the ratio of actual to possible alternations× 100.

3. Effectiveness of Genistein 

3.1.HypOoxia

In a study by Rumman et al. [19] impact of genistein on hypoxia-induced MI was investigated using male Swiss albino mice. The mice are continuously treated with 10,20 or 30 mg/kg/day of genistein p.o. for 28 days. A mice model for amnesia was developed based on hypoxia, by exposing the mice to a low level of oxygen (10%)daily for a similar duration as that for genistein treatment. Morris water maze (MWM), passive avoidance test (PAT), and novel object recognition(NOR) were used to investigate the effects of genistein in ameliorating memory defects in amnesiac mice.

The results based on MWM showed that mice treated with genistein doses of 20 and 30 mg/kg exhibited a low latency and increase in crossing number at the platform quadrant. As for PAT, there was an increase in latency in the 20 and 30 mg/kg genistein groups. Lastly, in NOR, both groups of mice which received 20 and 30 mg/kg genistein showed an increase in exploratory behavior of the novel object as compared with that for the familiar object. Overall, the findings suggested that treatment with genistein can help reduce memory defects in hypoxia-induced MI.

3.2.Chronic Sleep Depreciation (CSD)

In another study by Lu et al. [20] the effects of genistein on chronic sleep deprivation (CSD)-induced MI was investigated in male Institute of Cancer Research (ICR) mice. The mice were treated with genistein (10,20, or 40 mg/kg/day)p.o.daily for 23 days. Induction of CSD was performed using an automated sleep interruption apparatus (SIA)which consisted of a stainless steel rotator that rotates for 1 min after a 2 min pause for 24h/day for a total of 14 days. Morris water maze (MWM), object location recognition(OLR), and novel object recognition(NOR) were used to assess the spatial and recognition memory of the CSD-induced mice.

For MWM, the genistein-treated group especially the 40 mg/kg group had a significantly decreased latency in finding the submerged platform. Additionally, in the probe test where the platform was removed, there was a considerable increase in the crossing numbers in the target quadrant among the genistein 20 and 40 mg/kg. The genistein-treated group (20 and 40 mg/kg) showed a notably increased discrimination index(DI as compared with the CSD group in OLR. In the NOR task, there was a significant elevation in the DI, especially among the genistein 20 and 40 mg/kg treatment groups. Overall, genistein treatment (especially 20 and 40mg/kg)is effective in alleviating memory defects induced by CSD.

3.3.Streptozotocin (STZ)

To investigate the neuroprotective effect of genistein against streptozotocin (STZ)-induced cognitive dysfunction, male Wistar rats were administered with streptozotocin (STZ) via an intracerebroventricular(i.c.v.)injection for a cumulative 3 mg/kg over two injections with a 48h interval [13]. The rats were treated with genistein 150 mg/kg/day p.o. for 90 days. The genistein-treated group showed lower latency to swim towards the platform during the Morris water maze(MWM) test trial. However, in the probe test, the time spent by the genistein-treated rats in the target quadrant was significantly longer than the other groups, indicating that genistein treatment showed promising results in ameliorating STZ-induced MI.

3.4.Scopolamine

Lu et al.[22] investigated the effects of genistein on scopolamine-induced MI in male Institute of Cancer Research mice. The mice were intraperitoneally(i.p.) administered with scopolamine 0.75 mg/kg/day for seven consecutive days. Genistein(10, 20, or 40 mg/kg/day, p.o.) was administered daily to the mice for 24 days. The behavioral tests involved were objected location recognition(OLR) and Morris water maze(MWM) for evaluation of spatial memory. In the OLR task, the genistein-treated group (40 mg/kg)showed a significant increase in the discrimination index(DI). In both the trial and probe tests of MWM, the genistein-treated group showed a lower escape latency to locate the submerged platform and showed higher crossing numbers in the target quadrant, indicating that genistein treatment can improve cognitive performance.

3.5. Lipopolysaccharides (LPS)

Shahmohammadi et al. [23] conducted a study on the effect of genistein treatment on lipopolysaccharide(LPS)-induced neuro-inflammation on male albino Wistar rats. Neuro-inflammation was induced by introducing 500 ug/kg/day LPS(i.p). The subsequent genistein treatment was performed for seven days at 10,50 or 100 mg/kg/day. Spatial and recognition memories were assessed using Y-maze, novel object discrimination (NOD), and passive avoidance task(PAT).In all three tests, genistein (50 and 100 mg/kg) yielded significant improvements in the parameters involved which further supports that genistein treatment can alleviate cognitive dysfunction.

3.6. Streptozotocin (STZ)-Induced Diabetes

An in vivo study was conducted by Rajput et al. [21] to investigate the neuroprotective role of genistein on SIZ-induced diabetes in male albino Swiss mice. Diabetes in the mice was induced by introducing 200 mg/kg of STZ through an i.p.route. Diabetes was induced to cause hyperglycemia in the mice, which in turn can cause ischemia-reperfusion (IR)-induced neuronal damage. Subsequently, genistein treatment was administered through i.p. to the diabetic mice (2.5,5, or 10 mg/kg/day) for 14 days. Spatial and retention memories were then evaluated by using an elevated plus maze(EPM) which resulted in a decline in the transfer latency time for the genistein (5 and 10 mg/kg)treatment groups in diabetic mice with IR. Overall, the findings strongly suggest that cognitive deficits can be reduced with genistein treatment.

3.7.Lead

Su et al. [24]evaluated the protective effect of genistein treatment on the lead level as a toxicant. Male Sprague-Dawley rats were orally administered (p.o.)with both lead and genistein at 1 mg/kg/day for 56 days. A Morris water maze (MWM) was used to evaluate the cognitive performance of the rats and lead influence. Genistein treatment significantly decreased the latency to the platform and caused higher crossing numbers in the target quadrant in both trial and probe tests, thus suggesting that genistein treatment can reduce the effect of MI.

3.8. Kainic Acid (KA)-Induced Seizure

In a study by Khodamoradi et al. [25], genistein treatment was investigated for its possible effect on kainic acid (KA)-induced seizure on female Wistar rats. KA-induced seizure resulted in MI and neuronal injuries. KA was administered to the rats via the intracerebroventricular（i.c.v.）route（0.5 μg/μL）. Subsequently， the introduction of KA to the rats was performed four days after genistein treatment at 0.5 and 5 mg/kg/day through i.p. A Morris water maze (MWM) was used to assess spatial memory. Overall, the results suggest positive effects of the genistein towards the KA-induced seizure mice. 

3.9.Aging

Neese et al. [26] investigated the aging-related cognitive deficits and studied the potential protective effects of genistein in alleviating the deficits. They utilized 14-month-old female Long-Evans rats to simulate the aging effects on cognitive performance. Both lever press and Skinner box delayed spatial alternation (DSA)and differential reinforcement of low rates of responding (DRL)were used to evaluate the working memory. Nevertheless, the results indicated that genistein is not effective in ameliorating cognitive deficits in an aged rat MI model. 

3.10.-. Amyloid

Bagheri et al. [27] scrutinized the neuroprotective effect of genistein treatment on β-amyloid induced MI.β-amyloid 1-40 was injected i.c.v. （4 μL） into male Wistar rats， followed by the oral introduction of genistein(10 mg/kg/day). Y-maze, passive avoidance test (PAT), and radial arm maze (RAM) tests were used to evaluate the cognitive performance in which the rats treated with genistein showed significant parameter increments in both Y-maze and PATwhile in RAM, there was no significant increase in the correct choices of arms or decrease in incorrect arm choices. Overall, the findings suggested that treatment with genistein can prevent β-amyloid induced MI.

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