Different paradigms of transcranial electrical stimulation induce structural changes in the CA1 region of the hippocampus in a rat model of Alzheimer's disease.

One of the prominent sign of Alzheimer's disease (AD) is structural changes in the hippocampus. Recently, the new methods used to treat this disease is transcranial electrical stimulation (tES). This study evaluated the effect of four primary standards of tES, including tDCS, tACS, tRNS, and tPCS on beta-amyloid 25-35 (Aß25-35)-induced structural changes in the CA1 region of hippocampus in male rats. For this purpose, rats weighing 250-275 g were selected, the cannula was embedded reciprocally into the hippocampi. Aß25-35 (5 µg/ 2.5 ml/ day) was infused reciprocally for four continuous days.Then, animals were then given tES for 6 days.Subsequently, structural changes in the hippocampal CA1 were evaluated using the stereological method. Aß25-35 resulted in loss of neurons (P < 0.01) and decreased hippocampal volume (P < 0.05). However, the administration of tES paradigms prevented these changes. The results proposed that through the improvement of hippocampal cell number and volume, tES paradigms can retain efficiency in remediating structural impairments in AD. From this, it can be concluded that other tES paradigms besides tDCS can also be considered for the treatment of AD.

Interactive Effects of Swimming High-Intensity Interval Training and Resveratrol Supplementation Improve Mitochondrial Protein Levels in the Hippocampus of Aged Rats.

Mitochondrial dysfunction and increased oxidative stress cause damage to cells which can lead to the aging process and age-related diseases. Antioxidants such as resveratrol and high-intensity exercise can benefit oxidative damage prevention. This study is aimed at evaluating the effects of swimming high-intensity interval training and resveratrol on mitochondrial metabolism key proteins, SIRT5, SOD1, and PDH-E1α, and the level of NAD+ as a cofactor in the deacetylation process in aged rat hippocampus. Forty-five male Wistar rats, aged 20 months, were randomly divided into five groups: control (C), Swimming High-Intensity Interval Training (HIIT) (S-HIIT), Swimming HIIT with resveratrol supplementation (S-HIIT-R), resveratrol supplementation (R), and solvent of resveratrol supplementation (SR). S-HIIT and resveratrol groups performed the exercise and received resveratrol (10 mg/kg/day, gavage) for six weeks. Western blot analysis was performed to determine the protein level in the hippocampus. The amount of SIRT5 and SOD1 proteins in the hippocampus increased. S-HIIT with resveratrol or resveratrol alone increased the PDH-E1α level significantly. The amount of NAD+ was analyzed by assay kit that was reduced in S-HIIT, S-HIIT-R, and SR groups compared to controls. The results showed that resveratrol and S-HIIT attenuated the age-related brain changes by increasing the expression of SOD1 and SIRT5 and reducing the level of NAD+ in the hippocampus. Considering these findings, S-HIIT and resveratrol supplementation could be proposed as strategies to attenuate age-related brain changes. Resveratrol alone and exercise through the regulation of crucial proteins and cofactors can influence mitochondrial metabolism and oxidative stress in the hippocampus of aged rats.

Different paradigms of transcranial electrical stimulation improve motor function impairment and striatum tissue injuries in the collagenase-induced intracerebral hemorrhage rat model.

BACKGROUND: In the horizon of therapeutic restrictions in intracerebral hemorrhage (ICH), recently, non-invasive transcranial electrical stimulation (tES) has achieved considerable prosperities. Translational studies have postulated that transcranial direct current stimulation (tDCS) and the other types of tES remain potentially a novel therapeutic option to reverse or stabilize cognitive and motor impairments. OBJECTIVE: The aim of this study was to comparatively evaluate the effects of the four main paradigms of tES, including tDCS, transcranial alternating (tACS), pulsed (tPCS), and random noise (tRNS) stimulations on collagenase-induced sensorimotor impairments and striatum tissue damage in male rats. METHODS: To induce ICH, 0.5 µl of collagenase was injected into the right striatum of male Sprague Dawley rats. One day after surgery, tES, was applied to the animals for seven consecutive days. Motor functions were appraised by neurological deficit score, rotarod, and wire hanging tests on the day before surgery and postoperative days 3, 7, and 14. After behavioral tests, brain tissue was prepared appropriately to perform the stereological evaluations. RESULTS: The results indicated that the application of the four tES paradigms (tDCS, tACS, tRNS, and tPCS) significantly reversed motor disorders in collagenase-induced ICH groups. Further, the motor function improvement of tACS and tRNS receiving rats in wire-hanging and rotarod tests were higher than the other two tES receiving groups. Structural changes and stereological assessments also confirmed the results of behavioral functions. CONCLUSION: Our findings suggest that in addition to tDCS application in the treatment of ICH, other tES paradigms, especially tACS and tRNS may be considered as add-on therapeutic strategies in stroke.

Treatment with edaravone improves the structure and functional changes in the hippocampus after chronic cerebral hypoperfusion in rat.

This study aimed to find out cellular and electrophysiological effects of the edaravone (EDR) administration following induction of vascular dementia (VaD) via bilateral-carotid vessel occlusion (2VO). The rats were randomly divided into control, sham, 2VO + V (vehicle), and 2VO + EDR groups. EDR was administered once a day from day 0-28 after surgery. The passive-avoidance, Morris water-maze, and open-field tests were used for evaluation of memory, locomotor, and anxiety. The field-potential recording was used for assessment of electrophysiological properties of the hippocampus; and after sacrificing, the cerebral hemispheres were removed for stereological study and evaluation of MDA levels. The long-term potentiation (LTP), paired-pulse ratio (PPR), and input-output (I/O) curves were evaluated as indexes for long-term and short-term synaptic plasticity, and basal-synaptic transmission (BST), respectively. The 2VO led to increases in MDA level with considerable neuronal loss and decreases in the volume of the hippocampus, along with a reduction in the BST and LTP induction which was associated with a decrement in PPR and ultimate loss in memory with higher anxiety behavior. However, administration of EDR caused a decline in MDA and prevented the neural loss and volume of the hippocampus, rescued BST and LTP depression, improved memory and anxiety without any effects on PPR. Therefore, most likely through the improvement of MDA level, and the hippocampal cell number and volume, EDR leads to recovery of synaptic plasticity and behavioral performance. Because of the LTP rescue, without recovery of PPR, it is likely that the EDR improved LTP through the post-synaptic neurons.

Ameliorative Effects of Different Transcranial Electrical Stimulation Paradigms on the Novel Object Recognition Task in a Rat Model of Alzheimer Disease.

BACKGROUND: Treatment of Alzheimer as a disease that is associated with cognitive impairment has been associated with some restrictions. Recently, researchers have focused on non-pharmacological treatments, including non-invasive stimulation of the brain by transcranial electrical stimulation (tES). Four main paradigms of transcranial electrical current include transcranial direct current stimulation (tDCS), transcranial alternative current stimulation (tACS), transcranial random noise stimulation (tRNS), transcranial pulse current stimulation (tPCS). The tDCS is a possible new therapeutic option for patients with cognitive impairment, including Alzheimer disease. MATERIALS AND METHODS: The study was done on Sprague-Dawley male rats weighing 250-270 g. to develop Alzheimer's model, the cannula was implanted bilaterally into the hippocampus. Aß 25-35 (5µg/ 2.5µl/day) was microinjected bilaterally for 4 days. Then, an electrical stimulation paradigm was applied to the animal for 6 days. Animal cognitive capacity was evaluated on day 11 and 12 by novel object recognition (NOR) test. RESULTS: Our results showed that application of tDCS; tACS; tRNS and tPCS reversed beta-amyloid-induced impairment (P<0.05). The tRNS Group spent total exploration time around the objects compared to other groups (P<0.05). There was no significant difference between the four different paradigms in discrimination ratio and the percentage of total exploration time. CONCLUSION: The results of this study showed that the use of multiple sessions of different tES paradigms could improve Aß-induced memory impairment in the NOR test. Therefore, based on evidence, it can be expected that in addition to using tDCS, other stimulatory paradigms may also be considered in the treatment of AD.

Effect of Recombinant Insulin-like Growth Factor-2 Injected into the Hippocampus on Memory Impairment Following Hippocampal Intracerebral Hemorrhage in Rats.

BACKGROUND: Insulin-like growth factor 2 (IGF-2) is a growth factor and an anti-inflammatory cytokine that plays a pivotal role in memory. In this study, we examined the effect of recombinant IGF-2 on memory impairment due to intracerebral hemorrhage (ICH). Avoidance and recognition memory, locomotor activity, neurological deficit score (NDS), and the level of the IGF-2 gene expression were evaluated. MATERIALS AND METHODS: To induce ICH, 100 µL of autologous blood was injected into the left hippocampus of male Sprague Dawley rats. Recombinant IGF-2 was injected into the damaged hippocampus 30 minutes after the induction of ICH. Then, over two weeks, NDS, locomotor activity, passive avoidance, and novel object recognition (NOR) test were evaluated. Finally, the level of IGF-2 gene expression was evaluated by using the real-time polymerase chain reaction technique. RESULT: Our results indicated that recombinant IGF-2 injection significantly increased step-through latency (P<0.001) and total time spent in the dark box (P<0.01). However, no significant difference was seen in recognition memory and NDS. Locomotor activity did not significantly change in any group. A significantly reduced level of IGF-2 was observed after two weeks (P<0.05). CONCLUSION: The results of this study show that a single dose of recombinant IGF-2 injection can influence hippocampus-dependent memories. Importantly, IGF-2 did not change locomotor activity and NDS after two weeks, which probably represents its specific function in memory.

Agmatine protects against intracerebroventricular streptozotocin-induced water maze memory deficit, hippocampal apoptosis and Akt/GSK3ß signaling disruption.

Centrally administered streptozotocin (STZ), is known to cause Alzheimer׳s like memory deterioration. It mainly affects insulin signaling pathways such as PI3/Akt and GSK-3ß which are involved in cell survival. Previous studies indicate that STZ increases the ratio of Bax/Bcl-2 and thereby induces caspase-3 activation and apoptosis. Agmatine, a polyamine derived from l-arginine decarboxylation, is recently shown to exert some neuroprotective effects. This study aimed to assess if agmatine reverses STZ-induced memory deficits, hippocampal Akt/GSK-3ß signaling disruption and caspase-3 activation. Adult male Sprague-Dawely rats weighing 200-250 g were used. The canules were implanted bilaterally into lateral ventricles. STZ was administered on days 1 and 3 (3 mg/kg) and agmatine treatment (40 or 80 mg/kg) was started from day 4 and continued in an every other day manner till day 14. The animal׳s learning and memory capability was assessed on days 15-18 using Morris water maze. After complement of behavioral studies the hippocampi was isolated and the amounts of hippocampal cleaved caspase-3 (the landmark of apoptosis), Bax/Bcl-2 ratio, total and phosphorylated forms of GSK-3ß and Akt were analyzed by western blot. The results showed that agmatine in 80 but not 40 mg/kg reversed the memory deterioration induced by STZ. Western blot analysis revealed that STZ prompted elevation of caspase-3; Bax/Bcl-2 ratio and disrupted Akt/GSK-3ß signaling in the hippocampus. Agmatine treatment prevented apoptosis and Akt/GSK-3ß signaling impairment induced by STZ. This study disclosed that agmatine treatment averts not only STZ-induced memory deterioration but also hippocampal apoptosis and Akt/GSK-3ß signaling disruption.