Reduction Of Neurodegeneration Research Articles

The HOPE4MCI study: AGB101 treatment reduces entorhinal cortex atrophy in patients with amnestic mild cognitive impairment due to Alzheimer’s Disease who are ApoE‐4 non‐carriers

AbstractBackgroundHippocampal hyperactivity is a hallmark of prodromal Alzheimer’s disease (AD) that predicts progression in patients with amnestic mild cognitive impairment (aMCI). AGB101 is an extended‐release formulation of levetiracetam in the dose range previously demonstrated to normalize hippocampal activity and improve cognitive performance in aMCI. The HOPE4MCI clinical trial used a 78‐week protocol to assess progression in amyloid‐positive patients with MCI due to AD. Mohs et al. (2024) reported the clinical/cognitive results showing that ApoE‐4 non‐carriers had a more favorable treatment effect of AGB101 over the 78‐week duration of the study. Here we report effects of AGB101 on biomarkers of AD in those patients.MethodsForty‐four participants who completed the 78‐week protocol were ApoE‐4 non‐carriers. Structural MRI scans obtained in the study at baseline and after 78 weeks were analyzed using the Automated Segmentation of Hippocampal Subfields (ASHS) software providing volume measures of key structures of the medial temporal lobe relevant to AD progression. Blood samples collected at 78 weeks in the study were also analyzed for plasma biomarkers in those participants.ResultsTreatment with AGB101 significantly reduced atrophy in the left entorhinal cortex (p < 0.05) compared to placebo. Reduced atrophy in the entorhinal cortex was significantly correlated with the change in CDR‐SB score (r = ‐0.511) over 78 weeks, as well as with biomarkers of neurodegeneration neurofilament light (NfL; r = ‐0.382) and glial fibrillary acidic protein (GFAP; r = ‐0.398) collected at completion of the protocol.ConclusionAs reported in Mohs et al. (2024), progression on the primary clinical/cognitive endpoint of the Clincial Dementia Rating Scale Sum of Boxes score (CDR‐SB) occurred over the 78‐week protocol in the HOPE4MCI study and non‐carriers of ApoE4 treated with AGB101 showed a substantially more favorable effect than carriers. Here we report that treatment with AGB101, in those participants significantly reduced atrophy of the entorhinal cortex. That reduction in atrophy was significantly coupled with the change in CDR‐SB and with plasma biomarkers of disease. These exploratory analyses would be consistent with a reduction in neurodegeneration in the non‐carriers of ApoE4 treated with AGB101 prior to a clinical diagnosis of dementia.

The HOPE4MCI study: AGB101 treatment slows progression of entorhinal cortex atrophy in APOE ε4 non‐carriers with mild cognitive impairment due to Alzheimer's disease

AbstractIntroductionHippocampal hyperactivity is a hallmark of prodromal Alzheimer's disease (AD) that predicts progression in patients with amnestic mild cognitive impairment (aMCI). AGB101 is an extended‐release formulation of levetiracetam in the dose range previously demonstrated to normalize hippocampal activity and improve cognitive performance in aMCI. The HOPE4MCI study was a 78‐week trial to assess the progression of MCI due to AD. As reported in Mohs et al., the decline in the Clinical Dementia Rating Sum of Boxes score (CDR‐SB) was reduced by 40% in apolipoprotein E (APOE) ε4 non‐carriers over the 78‐week duration of the study with a negligible effect in carriers. Here we report an exploratory analysis of the effects of AGB101 on neuroimaging and biomarker measures in the 44 APOE ε4 non‐carriers who completed the 78‐week protocol.MethodsStructural magnetic resonance imaging scans obtained at baseline and after 78 weeks were analyzed using the Automated Segmentation of Hippocampal Subfields software providing volume measures of key structures of the medial temporal lobe relevant to AD progression. Blood samples collected at 78 weeks in the study were analyzed for plasma biomarkers.ResultsTreatment with AGB101 significantly reduced atrophy of the left entorhinal cortex (ERC) compared to placebo. This reduction in atrophy was correlated with less decline in the CDR‐SB score over 78 weeks and with lower neurofilament light chain (NfL), a marker of neurodegeneration.DiscussionThe HOPE4MCI study showed that APOE ε4 non‐carriers treated with AGB101 demonstrated a substantially more favorable treatment effect compared to carriers. Here we report that treatment with AGB101 in non‐carriers of APOE ε4 significantly reduced atrophy of the left ERC over 78 weeks. That reduction in atrophy was closely coupled with the change in CDR‐SB and with plasma NfL indicative of neurodegeneration in the brain. These exploratory analyses are consistent with a reduction in neurodegeneration in APOE ε4 non‐carriers treated with AGB101 before a clinical diagnosis of dementia.Highlights AGB101 slows entorhinal cortex (ERC) atrophy in apolipoprotein E (APOE) ε4 non‐carriers with mild cognitive impairment (MCI) due to Alzheimer's disease (AD). Slowing ERC atrophy by AGB101 is associated with less Clinical Dementia Rating Sum of Boxes decline. Slowing ERC atrophy by AGB101 is associated with lower neurofilament light chain. AGB101 treatment reduces neurodegeneration in APOE ε4 non‐carriers with MCI due to AD.

Significant dose‐dependent reduction in neurofilament light chain concentration in plasma with oral tau aggregation inhibitor hydromethylthionine mesylate

AbstractBackgroundHydromethylthionine mesylate (HMTM) is a potent oral tau aggregation inhibitor. Recent results from Study TRx‐237‐039 (LUCIDITY) suggest strong effects on cognitive and functional decline and progression of brain atrophy. We investigated the effect of HMTM on change in the plasma biomarker neurofilament light chain (NfL) in LUCIDITY. NfL is a clinically accessible and established biomarker for neurodegeneration that is known to be correlated with measures of clinical decline and brain atrophy in AD and MCI due to AD (MCI‐AD).MethodLUCIDITY is a double‐blind randomised controlled Phase 3 clinical trial comparing change over 12 months in cognitive, functional and brain atrophy outcomes at HMTM doses of 16 mg/day, 8 mg/day and methylthioninium chloride (MTC) at a dose of 4 mg twice weekly as a control in a 4:1:4 randomisation, with a subsequent 12 month blinded open‐label extension phase in which all participants received 16 mg/day.ResultBaseline and 12‐month NfL plasma levels were available as randomised in 161/185 participants receiving HMTM 16 mg/day, 38/48 receiving HMTM 8 mg/day and 136/185 receiving MTC 8 mg/week. The corresponding prespecified analysis model showed a 93% reduction in the change in NfL levels relative to control for HMTM 16 mg/day overall (p = 0.0278). Reduction in NfL change in the MCI‐AD subgroup was significant also at HMTM 8 mg/day (p = 0.0242). In the AD subgroup, there were directional dose‐dependent trends that did not reach statistical significance. Change in NfL level at 12 months was significantly correlated with change in ADAS‐cog11 (p = 0.0038) and whole brain volume (p = 0.0359) over 24 months.ConclusionThese results demonstrate that the orally administered tau aggregation‐inhibitor, HMTM, is able to produce a significant dose‐dependent reduction in neurodegeneration in AD as measured by change in plasma NfL levels.

Microglia-specific knock-out of NF-κB/IKK2 increases the accumulation of misfolded α-synuclein through the inhibition of p62/sequestosome-1-dependent autophagy in the rotenone model of Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder worldwide, with a greater prevalence in men than women. The etiology of PD is largely unknown, although environmental exposures and neuroinflammation are linked to protein misfolding and disease progression. Activated microglia are known to promote neuroinflammation in PD, but how environmental agents interact with specific innate immune signaling pathways in microglia to stimulate conversion to a neurotoxic phenotype is not well understood. To determine how nuclear factor kappa B (NF-κB) signaling dynamics in microglia modulate neuroinflammation and dopaminergic neurodegeneration, we generated mice deficient in NF-κB activation in microglia (CX3CR1-Cre::IKK2fl/fl ) and exposed them to 2.5 mg/kg/day of rotenone for 14 days, followed by a 14-day post-lesioning incubation period. We postulated that inhibition of NF-κB signaling in microglia would reduce overall inflammatory injury in lesioned mice. Subsequent analysis indicated decreased expression of the NF-κB-regulated autophagy gene, sequestosome 1 (p62), in microglia, which is required for targeting ubiquitinated α-synuclein (α-syn) for lysosomal degradation. Knock-out animals had increased accumulation of misfolded α-syn within microglia, despite an overall reduction in neurodegeneration. Interestingly, this occurred more prominently in males. These data suggest that microglia play key biological roles in the degradation and clearance of misfolded α-syn and this process works in concert with the innate immune response associated with neuroinflammation. Importantly, the accumulation of misfolded α-syn protein aggregates alone did not increase neurodegeneration following exposure to rotenone but required the NF-κB-dependent inflammatory response in microglia.

What Do Randomized Controlled Trials Inform Us About Potential Disease-Modifying Strategies for Parkinson's Disease?

Research advances have shed new insight into cellular pathways contributing to PD pathogenesis and offer increasingly compelling therapeutic targets. In this review, we made a broad survey of the published literature that report possible disease-modifying effects on PD. While there are many studies that demonstrate benefits for various therapies for PD in animal and human studies, we confined our search to human "randomised controlled trials" and with the key words "neuroprotection" or "disease-modifying". It is hoped that through studying the results of these trials, we might clarify possible mechanisms that underlie idiopathic PD. This contrasts with studying the effect of pathophysiology of familial PD, which could be carried out by gene knockouts and animal models. Randomised controlled trials indicate promising effects of MAO-B inhibitors, dopamine agonists, NMDA receptorantagonists, metabotropic glutamate receptor antagonists, therapies related to improving glucose utilization and energy production, therapies related to reduction of excitotoxicity andoxidative stress, statin use, therapies related to iron chelation, therapies related to the use of phytochemicals, and therapies related to physical exercise and brain reward pathwayon slowing PD progression. Cumulatively, these approaches fall into two categories: direct enhancement of dopaminergic signalling, and reduction of neurodegeneration. Overlaps between the two categories result in challenges in distinguishing between symptomatic versus disease-modifying effects with current clinical trial designs. Nevertheless, a broad-based approach allows us to consider all possible therapeutic avenues which may be neuroprotective. While the traditional standard of care focuses on symptomatic management with dopaminergic drugs, more recent approaches suggest ways to preserve dopaminergic neurons by attenuating excitotoxicity and oxidative stress.

Phikud Navakot extract attenuates lipopolysaccharide-induced inflammatory responses through inhibition of ERK1/2 phosphorylation in a coculture system of microglia and neuronal cells

Ethnopharmacological relevancePhikud Navakot (PN), a mixture of nine herbal plants, is an ancient Thai traditional medicine used for relieving circulatory disorders and dizziness. PN has also shown anti-inflammatory effects in rats with acute myocardial infarction. Moreover, phytochemical-inhibiting neuroinflammation, including gallic acid, vanillic acid, ferulic acid, and rutin were detected in PN extract; however, the anti-neuroinflammatory activity of PN extract and its components in a coculture system of microglia and neuronal cells is limited. ObjectiveTo investigate the anti-neuroinflammatory activities of PN on lipopolysaccharide (LPS)-induced inflammation in a coculture system of microglia and neuronal cells. MethodsELISA and qRT-PCR were used to assess cytokine expression. The phosphorylation of mitogen-activated protein kinases (MAPKs) was determined by Western blotting. Microglia-mediated neuroinflammation was evaluated using a BV-2 microglia-N2a neuron transwell co-culture. ResultsPN extract and its component, gallic acid, decreased LPS-induced the mRNA expression of interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS), as well as IL-6 protein levels in both microglial monoculture and coculture systems. This was accompanied by a reduction in neurodegeneration triggered by microglia in N2a neurons with increased neuronal integrity markers (βIII tubulin and tyrosine hydroxylase (TH)). These effects were caused by the ability of PN extract to inhibit extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) activation. ConclusionThis is the first study to show that PN extract inhibits neurodegeneration in LPS-activated BV-2 microglia by targeting ERK signaling activity.

Adipose-Derived Mesenchymal Stem Cells Partially Compensating the Neurodegenerative Signs at The Behavioral, Physiological, and Molecular Levels in AD Rat Model

Alzheimer's disease (AD) is the most common form of dementia. Due to the multifaceted nature of AD pathology and limited understanding of its etiology, AD is difficult to be treated with currently available pharmaceuticals. Recent studies suggest that transplantation of mesenchymal stem cells might have therapeutic potential on several neurodegenerative disorders. In addition, it can ameliorate neuropathological deficits and physiological disorders in AD. The current study aims to evaluate the potential therapeutic effect of adipose-derived mesenchymal stem cells (ADMSCs) in AD rat model after the induction with AlCl3. After the induction phase, labeled ADMSCs have been injected intravenously. Open-field behavioral tests were conducted, serum β-amyloid levels, cholinesterase activity, and brain antioxidant status were evaluated. Besides, the expression of apoptotic and necrotic markers was quantified via RT-qPCR in brain tissues. Histopathological alterations in the brain were examined as well. Signs of dementia as manifested by behavioral tests have been recorded in AD rats, accumulation of β-amyloid in blood, reduced serum cholinesterase activity and both apoptotic and necrotic induction in brain tissues had been recorded at the end of the induction phase. All these alterations have been partially/fully compensated by the administration of ADMSCs, which proved their ability to penetrate the blood-brain barrier and home in the brain tissues. The molecular mechanism underlying the therapeutic effect of ADMSCs seems to be correlated with the reduction of neurodegeneration by upregulating the anti-apoptotic marker (Bcl2) and downregulating the pro-apoptotic markers (p53 and Bax) and necrotic factor (Tnfa) simultaneously.

Reduction of Neuro degeneration in Glaucoma by Transplanted stems Cells Precursors

Introduction: Glaucoma is a common neurodegenerative disease for which current therapies are often insufficient. The purpose of our investigation was to determine whether Oligodendrocyte Precursor Cells (OPCs), a type of neural stem cell, can protect Retinal Ganglion Cells (RGCs) from glaucomatous damage in vivo. Methods: Intraocular pressure was chronically increased by trabecular laser treatment delivered unilaterally to adult rat eyes. OPCs were isolated in vitro and then transplanted intra vitreally either before, or concurrent with, injury induction. Results: Transplanted OPCs were found to survive within the eye for at least 12 weeks and to localize close to the RGCs. Moreover, OPCs significantly enhanced the survival of RGCs in the glaucomatous eye, but only when concomitantly activated by inflammation.. Amelioration of RGC death was not attributable to inflammation but relied on an interaction between inflammatory cells and OPCs. Engrafted cells also displayed multipotentiality in vivo.

Reduction of Neuro Degeneration in Glaucoma by Transplanted Stems Cells Precursors

Reduction of Neuro Degeneration in Glaucoma by Transplanted Stems Cells Precursors

Reduction of Neuro degeneration in Glaucoma by Transplanted stems Cells Precursors

Introduction: Glaucoma is a common neurodegenerative disease for which current therapies are often insufficient. The purpose of our investigation was to determine whether Oligodendrocyte Precursor Cells (OPCs), a type of neural stem cell, can protect Retinal Ganglion Cells (RGCs) from glaucomatous damage in vivo. Methods: Intraocular pressure was chronically increased by trabecular laser treatment delivered unilaterally to adult rat eyes. OPCs were isolated in vitro and then transplanted intra vitreally either before, or concurrent with, injury induction. Results: Transplanted OPCs were found to survive within the eye for at least 12 weeks and to localize close to the RGCs. Moreover, OPCs significantly enhanced the survival of RGCs in the glaucomatous eye, but only when concomitantly activated by inflammation.. Amelioration of RGC death was not attributable to inflammation but relied on an interaction between inflammatory cells and OPCs. Engrafted cells also displayed multipotentiality in vivo.

Пифитрин-альфа тормозит дифференцировку вновь образованных клеток субгранулярной зоны зубчатой извилины у крыс линии Крушинского–Молодкиной при аудиогенном киндлинге

One of the main goal of modern neurobiology is search for approaches to prevent structural violations in the brain. In particular, damage to the hippocampus after epileptic activity. Epilepsy leads to an increase in proliferation in the hippocampal neurogenic niche - subgranular cells layer of dental gyrus. In recent years, there is a prevalent idea that new-born cells contribute to epileptogenesis to a greater extent than prevent neurodegenerative damage. We suggested that proapoptotic protein p53 can be one of possible therapeutic targets for epilepsy and neurodegenerative consequences of this disease.In present work, we used The Krushinsky - Molodkina (KM) inbred rat strain. This strain is genetically prone to audiogenic seizures (AGS). Audiogenic kindling induced epileptiform activity in the limbic system and the cortex. It has been shown that in initial stages of epileptogenesis 4 AGS lead to increase in proliferation, aberrant migration in hilus and acceleration of differentiation of newborn cells. We did not show any disturbance in apoptosis nor autophagy in early development of limbic epilepsy. Pifitrin-α (chemical inhibitor of p53) did not lead to changes in apoptosis and autophagy but caused increase in proliferation and migration of newborn cells in granular cell layer and hilus of dental gyrus. However, in a week after the last seizure the number of differentiated cells decreased despite a significant increase in the number of newborn cells in the group with inactivation of p53 compared to the vehicle control group. Decreased number of differentiated cells tells that pifitrin -α may be used as a potential therapeutic agent for reduction in neurodegeneration which is associated with epilepsy.

Fyn-tau Ablation Modifies PTZ-Induced Seizures and Post-seizure Hallmarks of Early Epileptogenesis.

Both Fyn and tau have been associated with neuronal hyperexcitability and neurotoxicity in many tauopathies, including Alzheimer's disease (AD). Individual genetic ablation of fyn or tau appears to be protective against aberrant excitatory neuronal activities in AD and epilepsy models. It is, however, still unknown whether ablation of both Fyn and tau can likely elicit more profound anti-seizure and neuroprotective effects. Here, we show the effects of genetic deletion of Fyn and/or tau on seizure severity in response to pentylenetetrazole (PTZ)-induced seizure in mouse models and neurobiological changes 24 h post-seizures. We used Fyn KO (fyn−/−), tau KO (tau−/−), double knockout (DKO) (fyn−/−/tau−/−), and wild-type (WT) mice of the same genetic background. Both tau KO and DKO showed a significant increase in latency to convulsive seizures and significantly decreased the severity of seizures post-PTZ. Although Fyn KO did not differ significantly from WT, in response to PTZ, Fyn KO still had 36 ± 8% seizure reduction and a 30% increase in seizure latency compared to WT. Surprisingly, in contrast to WT, Fyn KO mice showed higher mortality in <20 min of seizure induction; these mice had severe hydrocephalous. None of the tau−/− and DKO died during the study. In response to PTZ, all KO groups showed a significant reduction in neurodegeneration and gliosis, in contrast to WT, which showed increased neurodegeneration [especially, parvalbumin (PV)-GABAergic interneurons] and gliosis. DKO mice had the most reduced gliosis. Immunohistochemically, phospho-tau (AT8, pS199/S202), Fyn expression, as well as Fyn-tau interaction as measured by PLA increased in WT post-PTZ. Moreover, hippocampal Western blots revealed increased levels of AT8, tyrosine phospho-tau (pY18), and phosphorylated Src tyrosine family kinases (pSFK) in PTZ-treated WT, but not in KO, compared to respective controls. Furthermore, PV interneurons were protected from PTZ-induced seizure effects in all KO mice. The levels of inwardly rectifying potassium (Kir 4.1) channels were also downregulated in astrocytes in the WT post-PTZ, while its levels did not change in KO groups. Overall, our results demonstrated the role of Fyn and tau in seizures and their impact on the mediators of early epileptogenesis in PTZ model.

Propolis ameliorates cerebral injury in focal cerebral ischemia/reperfusion (I/R) rat model via upregulation of TGF-β1

Neuroprotective impact of transforming growth factor β1 (TGF-β1) is increasingly recognized in different brain injuries. Propolis exhibits a broad spectrum of biological and pharmacological properties including neuroprotective action. The objective of the investigation was to explore the involvement of TGF-β1 signaling in the neuroprotective mechanism of propolis in I/R rats. In this study, focal cerebral ischemia model was built by middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion. The investigation was carried out on 48 rats that were arranged into four groups (n = 12): the sham group, I/R control group, I/R + propolis (50 mg/kg) group and I/R + propolis (100 mg/kg) group. The results revealed that propolis preserved rats against neuronal injury induced by cerebral I/R. It significantly reduced neurological deficit scores and improved motor coordination and locomotor activity in I/R rats. Propolis antagonized the damage induced by cerebral I/R through suppression of malondialdehyde (MDA) and elevation of reduced glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), brain-derived neurotropic factor (BDNF) and dopamine levels in the brain homogenates of I/R rats. Other ameliorations were also observed based on reduction of neurodegeneration and histological alterations in the brain tissues. These results also proposed that the neuroprotective effect of propolis might be related to upregulation of TGF-β1 and suppressed matrix metallopeptidase-9 (MMP9) mRNA expression.

Animal Venom Peptides as a Treasure Trove for New Therapeutics Against Neurodegenerative Disorders.

Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and cerebral ischemic stroke, impose enormous socio-economic burdens on both patients and health-care systems. However, drugs targeting these diseases remain unsatisfactory, and hence there is an urgent need for the development of novel and potent drug candidates. Animal toxins exhibit rich diversity in both proteins and peptides, which play vital roles in biomedical drug development. As a molecular tool, animal toxin peptides have not only helped clarify many critical physiological processes but also led to the discovery of novel drugs and clinical therapeutics. Recently, toxin peptides identified from venomous animals, e.g. exenatide, ziconotide, Hi1a, and PcTx1 from spider venom, have been shown to block specific ion channels, alleviate inflammation, decrease protein aggregates, regulate glutamate and neurotransmitter levels, and increase neuroprotective factors. Thus, components of venom hold considerable capacity as drug candidates for the alleviation or reduction of neurodegeneration. This review highlights studies evaluating different animal toxins, especially peptides, as promising therapeutic tools for the treatment of different neurodegenerative diseases and disorders.

Expression of mGlu Receptor Genes in the Hippocampus After Intoxication with Trimethyltin.

A variety of localization and signaling properties of eight subtypes of metabotropic glutamate receptors (mGluRs) in the brain provide glutamate an important regulatory role in many processes, including neurodegeneration and repair of neuronal damage. To identify specific subtypes of mGluRs, which are involved in neurodegeneration process, we assessed expression levels of their genes under pathophysiological conditions. Using quantitative real-time RT-PCR analysis, we studied transcription levels of mGlu2-5 and mGlu7 genes in the hippocampus after its damage by neurotoxicant trimethyltin chloride (TMT) in Wistar rats. This organotin compound is known to cause neurodegeneration in the brain, especially in the hippocampus. Morphological studies confirmed neuronal damage in CA3-CA4 subfields of the hippocampus 6weeks after the treatment with TMT. Step-through passive avoidance test revealed memory deterioration in rat-treated TMT. Interestingly, 3 and 6weeks after the treatment with TMT, expression levels of the mGlu2 and mGlu7 genes were not changed in comparison to the control values while expression level of mGlu4 genes was upregulated throughout the whole studied period of TMT action. The dynamics of mGlu3 gene expression revealed the existence of neuroinflammation 3weeks after the treatment with TMT, which was further confirmed by the upregulation of cyclooxygenase-2 gene expression. The expression level of mGlu5 receptors was downregulated 6weeks after the treatment with TMT. Our results revealed a significant role of mGlu4, mGlu5, and mGlu3 receptors in the neurodegenerative/reparative processes in the hippocampus after the treatment with TMT. Ligands of these receptor subtypes can be, therefore, considered potential therapeutic targets for prevention or reduction of neurodegeneration.

Ginger and Propolis Exert Neuroprotective Effects against Monosodium Glutamate-Induced Neurotoxicity in Rats.

Central nervous system cytotoxicity is linked to neurodegenerative disorders. The objective of the study was to investigate whether monosodium glutamate (MSG) neurotoxicity can be reversed by natural products, such as ginger or propolis, in male rats. Four different groups of Wistar rats were utilized in the study. Group A served as a normal control, whereas group B was orally administered with MSG (100 mg/kg body weight, via oral gavage). Two additional groups, C and D, were given MSG as group B along with oral dose (500 mg/kg body weight) of either ginger or propolis (600 mg/kg body weight) once a day for two months. At the end, the rats were sacrificed, and the brain tissue was excised and levels of neurotransmitters, ß-amyloid, and DNA oxidative marker 8-OHdG were estimated in the brain homogenates. Further, formalin-fixed and paraffin-embedded brain sections were used for histopathological evaluation. The results showed that MSG increased lipid peroxidation, nitric oxide, neurotransmitters, and 8-OHdG as well as registered an accumulation of ß-amyloid peptides compared to normal control rats. Moreover, significant depletions of glutathione, superoxide dismutase, and catalase as well as histopathological alterations in the brain tissue of MSG-treated rats were noticed in comparison with the normal control. In contrast, treatment with ginger greatly attenuated the neurotoxic effects of MSG through suppression of 8-OHdG and β-amyloid accumulation as well as alteration of neurotransmitter levels. Further improvements were also noticed based on histological alterations and reduction of neurodegeneration in the brain tissue. A modest inhibition of the neurodegenerative markers was observed by propolis. The study clearly indicates a neuroprotective effect of ginger and propolis against MSG-induced neurodegenerative disorders and these beneficial effects could be attributed to the polyphenolic compounds present in these natural products.

Early depletion of CA1 neurons and late neurodegeneration in a mouse tauopathy model

Alzheimer’s disease (AD) and tauopathies, such as frontotemporal dementia (FTD), are characterized by formation of neurofibrillary tangles consisting of hyperphosphorylated tau. Further neuropathological characteristics include synaptic loss, neurodegeneration and brain atrophy. Here, we explored the association between hyperphosphorylated tau species, brain atrophy, synaptic and neuronal loss in a mouse model (rTg4510) carrying the human tau (hTau) P301L mutation found in a familiar form of FTD. We established that hTau expression during the first 6 postnatal weeks was important for the progression of tauopathy in rTg4510 mice. Short term suppression of postnatal hTau expression delayed the onset of tau pathology by approximately 6months in this model. Early postnatal hTau expression was detrimental to CA1 neurons of the hippocampus and reduced neuronal numbers in 6–10weeks young rTg4510 mice prior to the appearance of hyperphosphorylated hTau species in the hippocampus. Hyperphosphorylated hTau species emerged from 10 to 24weeks of age and were associated with increased ubiquitin levels, gliosis, and brain atrophy and preceded the synaptic loss and CA1 neurodegeneration that occurred at 48weeks of age. We present two consequences of hTau expression in CA1 in rTg4510 mice: an early decrease in neuron number already established prior to the presence of hyperphosphorylated tau species and a later neurodegeneration dependent on hyperphosphorylated tau. Neurodegeneration and synaptic protein loss were completely prevented when hTau expression was suppressed prior to the appearance of hyperphosphorylated tau species. Suppression of hTau expression after the onset of tau hyperphosphorylation and tangle pathology initiated at 16weeks partially rescued neuronal loss at 48weeks of age, while a reduction of neurodegeneration was no longer possible when hTau suppression was introduced as late as at 24weeks of age. Our results in rTg4510 mice argue that it is promising to lower hyperphosphorylated tau species at early stages of tau pathology to protect from neurodegeneration.

Neuroprotective Effects of the Glutamate Transporter Activator (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153) following Traumatic Brain Injury in the Adult Rat.

Traumatic brain injury (TBI) in humans and in animals leads to an acute and sustained increase in tissue glutamate concentrations within the brain, triggering glutamate-mediated excitotoxicity. Excitatory amino acid transporters (EAATs) are responsible for maintaining extracellular central nervous system glutamate concentrations below neurotoxic levels. Our results demonstrate that as early as 5 min and up to 2 h following brain trauma in brain-injured rats, the activity (Vmax) of EAAT2 in the cortex and the hippocampus was significantly decreased, compared with sham-injured animals. The affinity for glutamate (KM) and the expression of glutamate transporter 1 (GLT-1) and glutamate aspartate transporter (GLAST) were not altered by the injury. Administration of (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), a GLT-1 activator, beginning immediately after injury and continuing for 24 h, significantly decreased neurodegeneration, loss of microtubule-associated protein 2 and NeuN (+) immunoreactivities, and attenuated calpain activation in both the cortex and the hippocampus at 24 h after the injury; the reduction in neurodegeneration remained evident up to 14 days post-injury. In synaptosomal uptake assays, MS-153 up-regulated GLT-1 activity in the naïve rat brain but did not reverse the reduced activity of GLT-1 in traumatically-injured brains. This study demonstrates that administration of MS-153 in the acute post-traumatic period provides acute and long-term neuroprotection for TBI and suggests that the neuroprotective effects of MS-153 are related to mechanisms other than GLT-1 activation, such as the inhibition of voltage-gated calcium channels.

Adipose-brain crosstalk: do adipokines have a role in neuroprotection?

Accumulating evidence from epidemiological and experimental studies indicate that obesity, and its related metabolic consequences of insulin resistance and type 2 diabetes, are associated with accelerated cognitive decline (Yates et al., 2012). The etiology of neurodegeneration in obesity is undoubtedly complex, with vascular, metabolic, inflammatory, and structural changes all likely to play a role (Yates et al., 2012). The discovery of leptin in 1994 and the subsequent advancement in our understanding that adipose tissue is an endocrine organ that can communicate with the brain to regulate appetite (Zhang et al., 1994) brings about the intriguing possibility that adipose-brain crosstalk can regulate aspects of neuronal physiology and pathology (Aguilar-Valles et al., 2015). Indeed neurons have been shown to express receptors for various adipokines, indicating that factors released from adipose tissue have the potential to communicate directly with the brain. Research in this area is relatively new, and while epidemiological data points towards the negative consequences of adipose-brain crosstalk (Whitmer et al., 2005), some intriguing new studies highlight that the secretory profile of adipose tissue might be involved in reduction in neurodegeneration via maintenance of neuronal viability (Tezapsidis et al., 2009; Wan et al., 2015).

Aminoguanidine treatment ameliorates inflammatory responses and memory impairment induced by amyloid-beta 25–35 injection in rats

Alzheimer disease (AD) is a neurodegenerative disorder caused by accumulation of the amyloid-beta peptide (Aβ) in neuritic plaques. Its neurotoxic mechanisms are associated with inflammatory responses and nitrosative stress generation that promote expression of inducible nitric oxide synthase (iNOS) and increased nitric oxide causing neuronal death and memory impairment. Studies suggest that treatment with anti-inflammatory and anti-oxidant agents decreases the risk of developing AD. Aminoguanidine (AG) is an iNOS inhibitor with anti-inflammatory and anti-oxidant effects. In this study, we evaluated the effects of systemic administration of AG (100mg/kg/day for 4days) on spatial memory and inflammatory responses induced by an injection of Aβ25–35 [100μM] into the temporal cortex (TCx) of rats. A significant improvement of spatial memory was evident in the Aβ25–35-treated group at day 30 post-injection subjected to AG treatment; this effect was correlated with decreases in reactive gliosis, IL-1β, TNF-α, and nitrite levels, as well as a reduction in neurodegeneration in the TCx and hippocampus (Hp). These results suggest that AG treatment inhibited glia activation and cytokine release, which may help to counteract neurodegenerative events induced by the toxicity of Aβ.