Neurophysiological treatment effects of mesdopetam, pimavanserin and clozapine in a rodent model of Parkinson's disease psychosis.

Psychosis in Parkinson's disease is a common phenomenon associated with poor outcomes. To clarify the pathophysiology of this condition and the mechanisms of antipsychotic treatments, we have here characterized the neurophysiological brain states induced by clozapine, pimavanserin, and the novel prospective antipsychotic mesdopetam in a rodent model of Parkinson's disease psychosis, based on chronic dopaminergic denervation by 6-OHDA lesions, levodopa priming, and the acute administration of an NMDA antagonist. Parallel recordings of local field potentials from eleven cortical and sub-cortical regions revealed shared neurophysiological treatment effects for the three compounds, despite their different pharmacological profiles, involving reversal of features associated with the psychotomimetic state, such as a reduction of aberrant high-frequency oscillations in prefrontal structures together with a decrease of abnormal synchronization between different brain regions. Other drug-induced neurophysiological features were more specific to each treatment, affecting network oscillation frequencies and entropy, pointing to discrete differences in mechanisms of action. These findings indicate that neurophysiological characterization of brain states is particularly informative when evaluating therapeutic mechanisms in conditions involving symptoms that are difficult to assess in rodents such as psychosis, and that mesdopetam should be further explored as a potential novel antipsychotic treatment option for Parkinson psychosis.

Optogenetic stimulation of entorhinal cortex reveals the implication of insulin signaling in adult rat's hippocampal neurogenesis.

Adult neurogenesis in the hippocampal dentate gyrus plays a critical role in learning and memory. Projections originating from entorhinal cortex, known as the perforant pathway, provide the main input to the dentate gyrus and promote neurogenesis. However, neuromodulators and molecular changes mediating neurogenic effects of this pathway are not yet fully understood. Here, by means of an optogenetic approach, we investigated neurogenesis and synaptic plasticity in the hippocampus of adult rats induced by stimulation of the perforant pathway. The lentiviruses carrying hChR2 (H134R)-mCherry gene under the control of the CaMKII promoter were injected into the medial entorhinal cortex region of adult rats. After 21 days, the entorhinal cortex region was exposed to the blue laser (473 nm) for five consecutive days (30 min/day). The expression of synaptic plasticity and neurogenesis markers in the hippocampus were evaluated using molecular and histological approaches. In parallel, the changes in the gene expression of insulin and its signaling pathway, trophic factors, and components of mitochondrial biogenesis were assessed. Our results showed that optogenetic stimulation of the entorhinal cortex promotes hippocampal neurogenesis and synaptic plasticity concomitant with the increased levels of insulin mRNA and its signaling markers, neurotrophic factors, and activation of mitochondrial biogenesis. These findings suggest that effects of perforant pathway stimulation on the hippocampus, at least in part, are mediated by insulin increase in the dentate gyrus and subsequently activation of its downstream signaling pathway.

Entorhinal cortex stimulation induces dentate gyrus neurogenesis through insulin receptor signaling.

Deep brain stimulation (DBS) has been established as a therapeutically effective method to treat pharmacological resistant neurological disorders. The molecular and cellular mechanisms underlying the beneficial effects of DBS on the brain are not yet fully understood. Beside numerous suggested mechanisms, regulation of neurogenesis is an attractive mechanism through which DBS can affect the cognitive functions. Considering the high expression of insulin receptors in hippocampus and also impaired neurogenesis in diabetic brain, the present study aimed to examine the role of insulin receptor signaling in DBS induced neurogenesis. High frequency stimulation was applied on the entorhinal cortex of rats and then neurogenesis markers in the dentate gyrus region of the hippocampus were examined using molecular and histological methods in the sham, DBS and insulin receptor antagonist-treated groups. In parallel, the changes in insulin receptor signaling in the hippocampus and spatial learning and memory performance were also assessed. DBS promoted adult hippocampal neurogenesis and facilitated the spatial memory concomitant with changes in insulin receptor signaling parameters including IR, IRS2 and GSK3ß. Application of insulin receptor antagonist attenuated the DBS-induced neurogenesis. Our data emphasize that entorhinal cortex stimulation promotes adult hippocampal neurogenesis and facilitates spatial learning and memory at least partly through insulin receptors. Notably, GSK3ß inhibition can play a major role in the downstream of insulin receptor signaling in DBS induced neurogenesis.

Rat sciatic nerve reconstruction across a 30 mm defect bridged by an oriented porous PHBV tube with Schwann cell as artificial nerve graft.

An oriented poly(3-hydroxybutyrate-co-3-hydroxyvalerate) nerve conduit has been used to evaluate its efficiency based on the promotion of peripheral nerve regeneration in rats. The oriented porous micropatterned artificial nerve conduit was designed onto the micropatterned silicon wafers, and then their surfaces were modified with oxygen plasma to increase cell adhesion. The designed conduits were investigated by cell culture analyses with Schwann cells (SCs). The conduits were implanted into a 30 mm gap in sciatic nerves of rats. Four months after surgery, the regenerated nerves were monitored and evaluated by macroscopic assessments and histology and behavioral analyses. Results of cellular analyses showed suitable properties of designed conduit for nerve regeneration. The results demonstrated that in the polymeric graft with SCs, the rat sciatic nerve trunk had been reconstructed with restoration of nerve continuity and formatted nerve fibers with myelination. Histological results demonstrated the presence of Schwann and glial cells in regenerated nerves. Functional recovery such as walking, swimming, and recovery of nociceptive function was illustrated for all the grafts especially conduits with SCs. This study proves the feasibility of the artificial nerve graft filled with SCs for peripheral nerve regeneration by bridging a longer defect in an animal model.

The healing effect of unrestricted somatic stem cells loaded in collagen-modified nanofibrous PHBV scaffold on full-thickness skin defects.

Unrestricted somatic stem cells (USSCs) loaded in nanofibrous PHBV scaffold can be used for skin regeneration when grafted into full-thickness skin defects of rats. Nanofibrous PHBV scaffolds were designed using electrospinning method and then, modified with the immobilized collagen via the plasma method. Afterward, the scaffolds were evaluated using scanning electron microscopy, physical and mechanical assays. In this study; nanofibrous PHBV scaffolds loaded with and without USSCs were grafted into the skin defects. The wounds were subsequently investigated at 21 days after grafting. Results of mechanical and physical analyses showed good resilience and compliance to movement as a skin graft. In animal models; all study groups excluding the control group exhibited the most pronounced effect on wound closure, with the statistically significant improvement in wound healing being seen on post-operative Day 21. Histological and immunostaining examinations of healed wounds from all groups, especially the groups treated with stem cells, showed a thin epidermis plus recovered skin appendages in the dermal layer. Thus, the graft of collagen-coated nanofibrous PHBV scaffold loaded with USSC showed better results during the healing process of skin defects in rat model.

Berberine chloride improved synaptic plasticity in STZ induced diabetic rats.

Previous studies indicated that diabetes affects synaptic transmission in the hippocampus, leading to impairments of synaptic plasticity and defects in learning and memory. Although berberine treatment ameliorates memory impairment and improves synaptic plasticity in streptozotocin (STZ) induced diabetic rats, it is not clear if the effects are pre- or post-synaptic or both. The aim of this study was to evaluate the effects of berberine chloride on short-term plasticity in inhibitory interneurons in the dentate gyrus of STZ-induced diabetic rats. Experimental groups included: The control, control berberine treated (100 mg/kg), diabetic and diabetic berberine treated (50,100 mg/kg/day for 12 weeks) groups. The paired pulse paradigm was used to stimulate the perforant pathway and field excitatory post-synaptic potentials (fEPSP) were recorded in dentate gyrus (DG). In comparison with control, paired pulse facilitation in the diabetic group was significantly increased (P < 0.01) and this effect prevented by chronic berberine treatment (50,100 mg/kg). However, there were no differences between responses of the control berberine 100 mg/kg treated and diabetes berberine treated (50 and 100 mg/kg) groups as compared to the control group. The present results suggest that the pre-synaptic component of synaptic plasticity in the dentate gyrus is affected under diabetic conditions and that berberine prevents this effect.

The effect of ghrelin on MK-801 induced memory impairment in rats.

Accumulating evidence indicates that the brain-gut peptide ghrelin which is expressed in hippocampus improves memory and learning processes. The MK-801, a noncompetitive NMDA receptor antagonist, has also shown amnesic properties in animal model. The current study was to find out whether intracerebroventricular administration of ghrelin can prevent amnesia induced by MK-801 in rats. A week after the surgery, during which cannuals were implanted in the lateral ventricular, the animals were trained and tested in a step-through type passive avoidance task. Memory retrieval was measured by step-through latency (STL) and total time in dark compartments (TDC). In the first series of experiments, we established a dose-response relationship for ghrelin on the passive avoidance paradigm. In the second set of experiments, animals were divided to two groups. In the first group, MK-801 (0.075, 0.15 and 0.3mg/kg) was injected intraperitoneally (i.p.) immediately after the acquisition session and in the second group MK-801 (same doses) was injected (i.p.) 30 min before the retention session. Analysis of data showed that in both groups, MK-801 impaired learning and memory. In the third set of experiments, administration of ghrelin (200 ng/rat) right after the acquisition session (i.e. before MK-801 injection) improved the MK-801 induced memory impairment, but administration of ghrelin before retrieval session did not affect the MK-801 induced memory impairment. These results show an interaction between ghrelin and glutamatergic system. A novel finding in this study is that ghrelin can prevent amnesia produced by NMDA antagonist in rats when injected in post-training phase.

Kindling-induced learning deficiency and possible cellular and molecular involved mechanisms.

Hippocampus learning disturbance is a major symptom of patients with seizure, hence hippocampal dysfunction has essential role in worsening the disease. Hippocampal formation includes neurons and myelinated fibers that are necessary for acquisition and consolidation of memory, long-term potentiation and learning activity. The exact mechanism by which seizure can decrease memory and learning activity of hippocampus remains unknown. In the present study, electrical kindling-induced learning deficit in rats was evaluated by Morris water maze (MWM) test. The hippocampus was removed and changes in neurons and myelin sheaths around hippocampal fibers were investigated using histological and immunohistochemical methods. Demyelination was assessed by luxol fast blue staining, and immunohistological staining of myelin-binding protein (MBP). The TUNEL assay was used for evaluation of neuronal apoptosis and the glial fibriliary acetic protein (GFAP) was used for assessment of inflammatory reaction. The results indicated that electrical kindling of hippocampus could induce deficiency in spatial learning and memory as compared to control group. In addition, electrical kindling caused damage to the myelin sheath around hippocampal fibers and produced vast demyelination. Furthermore, an increase in the number of apoptotic cells in hippocampal slices was observed. In addition, inflammatory response was higher in kindled animals as compared to the control group. The results suggested that the decrease in learning and memory in kindled animals is likely due to demyelination and augmentation in apoptosis rate accompanied by inflammatory reaction in hippocampal neurons of kindled rats.

Hippocampal synaptic plasticity restoration and anti-apoptotic effect underlie berberine improvement of learning and memory in streptozotocin-diabetic rats.

Chronic diabetes mellitus initiates apoptosis and negatively affects synaptic plasticity in the hippocampus with ensuing impairments of learning and memory. Berberine, an isoquinoline alkaloid, exhibits anti-diabetic, antioxidant and nootropic effects. This study was conducted to evaluate the effect of berberine on hippocampal CA1 neuronal apoptosis, synaptic plasticity and learning and memory of streptozotocin (STZ)-diabetic rats. Long-term potentiation (LTP) in perforant path-dentate gyrus synapses was recorded for assessment of synaptic plasticity and field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude. PS amplitude and fEPSP significantly decreased in diabetic group versus control, and chronic berberine treatment (100mg/kg/day, p.o.) restored PS amplitude and fEPSP and ameliorated learning and memory impairment and attenuated apoptosis of pyramidal neurons in the CA1 area, as determined by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling method. In summary, chronic berberine treatment of STZ-diabetic rats significantly ameliorates learning and memory impairment and part of its beneficial effect could be attributed to improvement of synaptic dysfunction and anti-apoptotic property.

Attenuating the effect of Ghrelin on memory storage via bilateral reversible inactivation of the basolateral amygdale.

Previous studies have shown that Ghrelin increases memory retention. They have also indicated that amygdale is involved in memory storage. The present study examined the role of basolateral amygdala (BLA) in Ghrelin-induced retention improvement, using reversible inactivation of this region with lidocaine. Rats were bilaterally implanted with cannulae at the BLA. One week later, they received intra-BLA injection of lidocaine, saline or Ghrelin with 5 min interval immediately after training. 24-72 h after training, step-through latency (STL) was measured as learning and memory index. The results showed that injection of Ghrelin into the BLA produced a significant enhancement in retention, which was attenuated by injection of lidocaine into BLA. These finding indicate that the BLA is involved in mediating the memory-modulating effect of Ghrelin.

Netrin-1 improves spatial memory and synaptic plasticity impairment following global ischemia in the rat.

Cerebral ischemia, which is the second and most common cause of mortality, affects millions of individuals worldwide. The present study was performed to investigate whether intrahippocampal administration of netrin-1 could improve spatial memory impairment in radial arm maze task and restore long-term potentiation (LTP) in 4-vessel occlusion model of global ischemia. The results showed that intrahippocampal infusion of nerin-1 24 h after ischemia (at both doses of 400 and 800 ng) significantly ameliorated spatial memory impairment and at a dose of 800 ng was capable to improve synaptic dysfunction as observed by recovery of population spike component of basal evoked potential and LTP through enhancement of excitability and normalization of paired pulse response. Taken together, the present study shows that netrin-1 dose-dependently ameliorates spatial memory impairment and improves synaptic dysfunction as observed by recovery of population spike component of basal evoked potential and LTP in rats with global ischemia.

L-type calcium channel mediates anticonvulsant effect of cannabinoids in acute and chronic murine models of seizure.

The anticonvulsant activities of cannabinoid compounds have been shown in various models of seizure and epilepsy. At least, part of antiseizure effects of cannabinoid compounds is mediated through calcium (Ca(2+)) channels. The L-type Ca(2+) channels have been shown to be important in various epilepsy models. However, there is no data regarding the role of L-type Ca(2+) channels in protective action of cannabinoids on acute and chronic models of seizure. In this study, the effects of cannabinoid compounds and L-type Ca(2+) channels blockers, either alone or in combination were investigated using acute model of pentylenetetrazole (PTZ)-induced seizure in mice and chronic model electrical kindling of amygdala in rats. Pretreatment of mice with both cannabinoid CB1 receptor agonist arachidonyl-2'-chloroethylamide (ACEA) and endocannabinoid degradating enzyme inhibitor cyclohexylcarbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597) produced a protective effect against PTZ-induced seizure. Administration of various doses of the two L-type Ca(2+) channel blockers verapamil and diltiazem did not alter PTZ-induced seizure threshold. However, co-administration of verapamil and either ACEA or URB597 attenuated the protective effect of cannabinoid compounds against PTZ-induced seizure. Also, pretreatment of mice with diltiazem blocked the anticonvulsant activity of both ACEA and URB597. Moreover, (R)-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate (WIN55,212-2), the non-selective cannabinoid CB1 and CB2 receptor agonist showed anticonvulsant effect in amygdala-kindled rats. However, co-administration of WIN55,212-2 and verapamil attenuated the protective properties of WIN55,212-2. Our results showed that the anticonvulsant activity of cannabinoid compounds is mediated, at least in part, by L-type Ca(2+) channels in these two models of convulsion and epilepsy.