Amyloid-ß (25-35) induces the morphological alteration of dendritic spines and decreases NR2B and PSD-95 expression in the hippocampus.

Research on the memory impairment caused by the Amyloid-ß 25-35 (Aß25-35) peptide in animal models has provided an understanding of the causes that occurs in Alzheimer's disease. However, it is uncertain whether this cognitive impairment occurs due to disruption of information encoding and consolidation or impaired retrieval of stored memory. The aim of this study was to determine the effect of the Aß25-35 peptide on the morphology of dendritic spines and the changes in the expression of NR2B and PSD-95 in the hippocampus associated with learning and memory deficit. Vehicle or Aß25-35 peptide (0.1 µg/µL) was bilaterally administered into the CA1 subfield of the rat hippocampus, then tested for spatial learning and memory in the Morris Water Maze. On Day 39, the morphological changes in the CA1 of the hippocampus and dentate gyrus were examined via Golgi-Cox stain. It was observed that the Aß25-35 peptide administered in the CA1 region of the rat hippocampus induced changes to the morphology of dendritic spines and the expression of the NR2B subunit of the NMDA receptor co-localized with both the spatial memory and PSD-95 protein in the hippocampus of learning rats. We conclude that, in soluble form, the Aß25-35 peptide perturbs synaptic plasticity, specifically in the formation of new synapses, thus promoting the progression of memory impairment.

Intrapallidal injection of cannabidiol or a selective GPR55 antagonist decreases motor asymmetry and improves fine motor skills in hemiparkinsonian rats.

Cannabidiol (CBD) presents antiparkinsonian properties and neuromodulatory effects, possibly due to the pleiotropic activity caused at multiple molecular targets. Recently, the GPR55 receptor has emerged as a molecular target of CBD. Interestingly, GPR55 mRNA is expressed in the external globus pallidus (GPe) and striatum, hence, it has been suggested that its activity is linked to motor dysfunction in Parkinson's disease (PD). The present study aimed to evaluate the effect of the intrapallidal injection of both CBD and a selective GPR55 antagonist (CID16020046) on motor asymmetry, fine motor skills, and GAD-67 expression in hemiparkinsonian rats. The hemiparkinsonian animal model applied involved the induction of a lesion in male Wistar rats via the infusion of the neurotoxin 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle via stereotaxic surgery. After a period of twenty days, a second surgical procedure was performed to implant a guide cannula into the GPe. Seven days later, lysophosphatidylinositol (LPI), CBD, or CID16020046 were injected once a day for three consecutive days (from the 28th to the 30th day post-lesion). Amphetamine-induced turning behavior was evaluated on the 14th and 30th days post-injury. The staircase test and fine motor skills were evaluated as follows: the rats were subject to a ten-day training period prior to the 6-OHDA injury; from the 15th to the 19th days post-lesion, the motor skills alterations were evaluated under basal conditions; and, from the 28th to the 30th day post-lesion, the pharmacological effects of the drugs administered were evaluated. The results obtained show that the administration of LPI or CBD generated lower levels of motor asymmetry in the turning behavior of hemiparkinsonian rats. It was also found that the injection of CBD or CID16020046, but not LPI, in the hemiparkinsonian rats generated significantly superior performance in the staircase test, in terms of the use of the forelimb contralateral to the 6-OHDA-induced lesion, when evaluated from the 28th to the 30th day post-lesion. Similar results were also observed for superior fine motor skills performance for pronation, grasp, and supination. Finally, the immunoreactivity levels were found to decrease for the GAD-67 enzyme in the striatum and the ipsilateral GPe of the rats injected with CBD and CID16020046, in contrast with those lesioned with 6-OHDA. The results obtained suggest that the inhibitory effects of CBD and CID16020046 on GPR55 in the GPe could be related to GABAergic overactivation in hemiparkinsonism, thus opening new perspectives to explain, at a cellular level, the reversal of the motor impairment observed in PD models.

Neuropathological Aspects of SARS-CoV-2 Infection: Significance for Both Alzheimer's and Parkinson's Disease.

Evidence suggests that SARS-CoV-2 entry into the central nervous system can result in neurological and/or neurodegenerative diseases. In this review, routes of SARS-Cov-2 entry into the brain via neuroinvasive pathways such as transcribrial, ocular surface or hematogenous system are discussed. It is argued that SARS-Cov-2-induced cytokine storm, neuroinflammation and oxidative stress increase the risk of developing neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Further studies on the effects of SARS-CoV-2 and its variants on protein aggregation, glia or microglia activation, and blood-brain barrier are warranted.

The C-terminal domain of the heavy chain of tetanus toxin prevents the oxidative and nitrosative stress induced by acute toxicity of 1-methyl-4-phenylpyridinium, a rat model of Parkinson's disease.

The recombinant carboxyl-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) exerts neuroprotective and neurorestorative effects on the dopaminergic system of animal models of Parkinson's disease (PD). The present study aimed to determine the effect of the Hc-TeTx fragment on the markers of oxidative stress and nitrosative stress generated by the acute toxicity of 1-methyl-4-phenylpyridinium (MPP+). For this purpose, the Hc-TeTx fragment was administered once a day in three 20 µg/kg consecutive injections into the grastrocnemius muscle of the rats, with an intra-striatal unilateral injection of 1 µL of MPP+ [10 µg/mL] then administered in order to cause a dopaminergic lesion. The results obtained show that the rats treated with Hc-TeTx plus MPP+ presented an increase in the expression of tyrosine hydroxylase (TH), a significantly greater decrease in the levels of the markers of oxidative stress, nitrosative stress, and neurodegeneration than that observed for the group injured with only MPP+. Moreover, it was observed that total superoxide dismutase (SOD) and copper/zinc SOD activity increased with the administration of Hc-TeTx. Finally, immunoreactivity levels were observed to decrease for the levels of 3-nitrotyrosine and the glial fibrillary acidic protein in the ipsilateral striatum of the rats treated with Hc-TeTx plus MPP+, in contrast with those lesioned with MPP+ alone. Our results demonstrate that the recombinant Hc-TeTx fragment may be a potent antioxidant and, therefore, could be suggested as a therapeutic tool against the dopaminergic neuronal impairment observed in the early stages of PD.

The Chronic Oral Administration of Clobenzorex or Amphetamine Decreases Motor Behavior and Induces Glial Activation in the Striatum Without Dopaminergic Degeneration.

Described as amphetamine-like due to their structural and stimulant similarities, clobenzorex is one of the five most-commonly used drugs in Mexico for the treatment of obesity. Various studies have shown that amphetamines induce dopaminergic neurotoxicity and neuroinflammation in the striatum, symptoms which are associated with motor damage. For this reason, the present study aimed to evaluate the effect of chronic clobenzorex administration on motor behaviors, TH immunoreactivity, gliosis, and the neurodegenerative process in the striatum and substantia nigra pars compacta (SNpc). The present research was conducted on three experimental groups of male Wistar rats: the vehicle group, the amphetamine group (2 mg/kg), and the clobenzorex group (30 mg/kg). All groups were subject to oral administration every 24 h for 31 days. Motor activity and motor coordination were evaluated in the open field test and the beam walking test, respectively. The animals were euthanized after the last day of treatment to enable the extraction of their brains for the evaluation of tyrosine hydroxylase (TH) levels, the immunoreactivity of the glial cells, and the neurodegeneration of both the striatum and SNpc via amino-cupric-silver stain. The results obtained show that amphetamine and clobenzorex administration decrease motor activity and motor coordination in the beam walking test and cause increased gliosis in the striatum, while no significant changes were observed in terms of immunoreactivity to TH and neurodegeneration in both the striatum and SNpc. These results suggest that the chronic administration of clobenzorex may decrease motor function in a manner similar to amphetamine, via the neuroadaptive and non-neurotoxic changes caused to the striatum under this administration scheme.

Disturbance of the Glutamate-Glutamine Cycle, Secondary to Hepatic Damage, Compromises Memory Function.

Glutamate fulfils many vital functions both at a peripheral level and in the central nervous system (CNS). However, hyperammonemia and hepatic failure induce alterations in glutamatergic neurotransmission, which may be the main cause of hepatic encephalopathy (HE), an imbalance which may explain damage to both learning and memory. Cognitive and motor alterations in hyperammonemia may be caused by a deregulation of the glutamate-glutamine cycle, particularly in astrocytes, due to the blocking of the glutamate excitatory amino-acid transporters 1 and 2 (EAAT1, EAAT2). Excess extracellular glutamate triggers mechanisms involving astrocyte-mediated inflammation, including the release of Ca2+-dependent glutamate from astrocytes, the appearance of excitotoxicity, the formation of reactive oxygen species (ROS), and cell damage. Glutamate re-uptake not only prevents excitotoxicity, but also acts as a vital component in synaptic plasticity and function. The present review outlines the evidence of the relationship between hepatic damage, such as that occurring in HE and hyperammonemia, and changes in glutamine synthetase function, which increase glutamate concentrations in the CNS. These conditions produce dysfunction in neuronal communication. The present review also includes data indicating that hyperammonemia is related to the release of a high level of pro-inflammatory factors, such as interleukin-6, by astrocytes. This neuroinflammatory condition alters the function of the membrane receptors, such as N-methyl-D-aspartate (NMDA), (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) AMPA, and γ-aminobutyric acid (GABA), thus affecting learning and spatial memory. Data indicates that learning and spatial memory, as well as discriminatory or other information acquisition processes in the CNS, are damaged by the appearance of hyperammonemia and, moreover, are associated with a reduction in the production of cyclic guanosine monophosphate (cGMP). Therefore, increased levels of pharmacologically controlled cGMP may be used as a therapeutic tool for improving learning and memory in patients with HE, hyperammonemia, cerebral oedema, or reduced intellectual capacity.

The therapeutic potential of galectin-1 and galectin-3 in the treatment of neurodegenerative diseases.

Introduction: Neuroinflammation has been proposed as a common factor and one of the main inducers of neuronal degeneration. Galectins are a group of ß-galactoside-binding lectins, that play an important role in the immune response, adhesion, proliferation, differentiation, migration and cell growth. Up to 15 members of the galectin's family have been identified; however, the expression of galectin-1 and galectin-3 has been considered a key factor in neuronal regeneration and modulation of the inflammatory response. Galectin-1 is necessary to stimulate the secretion of neurotrophic factors in astrocytes and promoting neuronal regeneration. In contrast, galectin-3 fosters the proliferation of microglial cells and modulates cellular apoptosis, therefore these proteins are considered a useful alternative for the treatment of degenerative diseases.Areas covered: This review describes the roles of galectin-1 and galectin-3 in the modulation of neuroinflammation and their potential as therapeutic targets in the treatment for neurodegenerative diseases.Expert opinion: Although data in the literature vary, the effects of galectin-1 and galectin-3 on the activation and modulation of astrocytes and microglia has been described. Due to its anti-inflammatory effects, galectin-1 is proposed as a molecule with therapeutic potential, whereas the inhibition of galectin-3 could contribute to reduce the neuroinflammatory response in neurodegenerative diseases.

Cannabidiol as a Therapeutic Target: Evidence of its Neuroprotective and Neuromodulatory Function in Parkinson's Disease.

The phytocannabinoids of Cannabis sativa L. have, since ancient times, been proposed as a pharmacological alternative for treating various central nervous system (CNS) disorders. Interestingly, cannabinoid receptors (CBRs) are highly expressed in the basal ganglia (BG) circuit of both animals and humans. The BG are subcortical structures that regulate the initiation, execution, and orientation of movement. CBRs regulate dopaminergic transmission in the nigro-striatal pathway and, thus, the BG circuit also. The functioning of the BG is affected in pathologies related to movement disorders, especially those occurring in Parkinson's disease (PD), which produces motor and non-motor symptoms that involving GABAergic, glutamatergic, and dopaminergic neural networks. To date, the most effective medication for PD is levodopa (l-DOPA); however, long-term levodopa treatment causes a type of long-term dyskinesias, l-DOPA-induced dyskinesias (LIDs). With neuromodulation offering a novel treatment strategy for PD patients, research has focused on the endocannabinoid system (ECS), as it participates in the physiological neuromodulation of the BG in order to control movement. CBRs have been shown to inhibit neurotransmitter release, while endocannabinoids (eCBs) play a key role in the synaptic regulation of the BG. In the past decade, cannabidiol (CBD), a non-psychotropic phytocannabinoid, has been shown to have compensatory effects both on the ECS and as a neuromodulator and neuroprotector in models such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and reserpine, as well as other PD models. Although the CBD-induced neuroprotection observed in animal models of PD has been attributed to the activation of the CB1 receptor, recent research conducted at a molecular level has proposed that CBD is capable of activating other receptors, such as CB2 and the TRPV-1 receptor, both of which are expressed in the dopaminergic neurons of the nigro-striatal pathway. These findings open new lines of scientific inquiry into the effects of CBD at the level of neural communication. Cannabidiol activates the PPARγ, GPR55, GPR3, GPR6, GPR12, and GPR18 receptors, causing a variety of biochemical, molecular, and behavioral effects due to the broad range of receptors it activates in the CNS. Given the low number of pharmacological treatment alternatives for PD currently available, the search for molecules with the therapeutic potential to improve neuronal communication is crucial. Therefore, the investigation of CBD and the mechanisms involved in its function is required in order to ascertain whether receptor activation could be a treatment alternative for both PD and LID.

The Acute Activation of the CB1 Receptor in the Hippocampus Decreases Neurotoxicity and Prevents Spatial Memory Impairment in Rats Lesioned with ß-Amyloid 25-35.

Given their anti-inflammatory properties, cannabinoids have been shown to be neuroprotective agents and to reduce excitotoxicity, through the activation of the Cannabinoid receptor type 1 (CB1r). These properties have led to CB1r being proposed as pharmacological targets for the treatment of various neurodegenerative diseases. Amyloid-ß 25-35 (Aß25-35) induces the expression of inducible nitric oxide synthase (iNOS) and increases nitric oxide (NO●) levels. It has been observed that increased NO● concentrations trigger biochemical pathways that contribute to neuronal death and cognitive damage. This study aimed to evaluate the neuroprotective effect of an acute activation of CB1r on spatial memory and its impact on iNOS protein expression, NO● levels, gliosis and the neurodegenerative process induced by the injection of Aß(25-35) into the CA1 subfield of the hippocampus. ACEA [1 µM/1 µL] and Aß(25-35) [100 µM/1 µL] and their respective vehicle groups were injected into the CA1 subfield of the hippocampus. The animals were tested for spatial learning and memory in the eight-arm radial maze, with the results revealing that the administration of ACEA plus Aß(25-35) improves learning and memory processes, in contrast with the Aß(25-35) group. Moreover, ACEA plus Aß(25-35) prevented both the increase in iNOS protein and NO● levels and the reactive gliosis induced by Aß(25-35). Importantly, neurodegeneration was significantly reduced by the administration of ACEA plus Aß(25-35) in the CA1 subfield of the hippocampus. The data obtained in the present research suggest that the acute early activation of CB1r is crucial for neuroprotection.

Neuroinflammation induced by the peptide amyloid-ß (25-35) increase the presence of galectin-3 in astrocytes and microglia and impairs spatial memory.

Galectins are animal lectins that bind to ß-galactosides, such as lactose and N-acetyllactosamine, contained in glycoproteins or glycolipids. Galectin-1 (Gal-1) and Galectin-3 (Gal-3) are involved in pathologies associated with the inflammatory process, cell proliferation, adhesion, migration, and apoptosis. Recent evidence has shown that the administration of Amyloid-ß 25-35 (Aß25-35) into the hippocampus of rats increases the inflammatory response that is associated with memory impairment and neurodegeneration. Galectins could participate in the modulation of the neuroinflammation induced by the Aß25-35. The aim of this study was to evaluate the presence of Gal-1 and Gal-3 in the neuroinflammation induced by administration of Aß25-35 into the hippocampus and to examine spatial memory in the Morris water maze. After the administration of Aß25-35, animals were tested for learning and spatial memory in the Morris water maze. Behavioral performance showed that Aß25-35 didn't affect spatial learning but did impair memory, with animals taking longer to find the platform. On the day 32, hippocampus was examined for astrocytes (GFAP), microglia (Iba1), Gal-1 and Gal-3 via immunohistochemical analysis, and the cytokines IL-1ß, TNF-α, IFN-γ by ELISA. This study's results showed a significant increase in the expression of Gal-3 in the microglia and astrocytes, while Gal-1 didn't increase in the dorsal hippocampus. The expression of galectins is associated with increased cytokines in the hippocampal formation of Aß25-35 treated rats. These findings suggest that Gal-3 could participate in the inflammation induced by administration of Aß25-35 and could be involved in the neurodegeneration progress and memory impairment.