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Inflammatory processes in the brain can exert important neuroprotective functions. However, in neurological and psychiatric disorders, it is often detrimental due to chronic microglial over-activation and the dysregulation of cytokines and chemokines. Growing evidence indicates the emerging yet prominent pathophysiological role of neuroinflammation in the development and progression of these disorders. Despite recent advances, there is still a pressing need for effective therapies, and targeting neuroinflammation is a promising approach. Therefore, in this study, we investigated the anti-neuroinflammatory potential of a marketed and quantified proprietary herbal extract of Ginkgo biloba leaves called EGb 761 (10-500 µg/mL) in BV2 microglial cells stimulated by LPS (10 ng/mL). Our results demonstrate significant inhibition of LPS-induced expression and release of cytokines tumor necrosis factor-α (TNF-α) and Interleukin 6 (IL-6) and chemokines C-X-C motif chemokine ligand 2 (CXCL2), CXCL10, c-c motif chemokine ligand 2 (CCL2) and CCL3 in BV2 microglial cells. The observed effects are possibly mediated by the mitogen-activated protein kinases (MAPK), p38 MAPK and ERK1/2, as well as the protein kinase C (PKC) and the nuclear factor (NF)-κB signaling cascades. The findings of this in vitro study highlight the anti-inflammatory properties of EGb 761 and its therapeutic potential, making it an emerging candidate for the treatment of neuroinflammatory diseases and warranting further research in pre-clinical and clinical settings.

It is an often-neglected fact that extracts derived from the very same plant can differ significantly in their phytochemical composition, and thus also in their pharmacokinetic and pharmacodynamic properties which are the basis for their clinical efficacy and safety. The Ginkgo biloba L. [ Ginkgoaceae ] special extract EGb 761 ® is one of the best-studied plant extracts in the world. In the present review, using that extract as a paradigm, we describe insights how climate, the harvest region, processing of the plant material, the drying process, the extraction solvents, and the details of the subsequent process steps substantially impact the quality and uniformity of the final extract. We highlight the importance of regulating active constituent levels and consistent reduction of undesired substances in herbal extracts. This is accomplished by a controlled production process and corresponding analytical specifications. In conclusion, since extracts derived from the same plant can have very different phytochemical compositions, results from pharmacological, toxicological and clinical studies gained with one specific extract cannot be extrapolated to other extracts that were generated using different production processes. We propose that the heterogenous nature of extracts should be meticulously considered when evaluating the efficacy and safety of plant-derived remedies., Competing Interests: All authors are employed by Dr. Willmar Schwabe GmbH and Co., KG, manufacturer of medicinal products containing the special extract from G. biloba leaves, EGb 761®., (Copyright © 2022 Kulić, Lehner and Dietz.)

BACKGROUND Cognitive symptoms persisting longer than 3 months after infection, such as memory loss, or difficulties concentrating, have been reported in up to one-third of patients after COVID-19. Evidence-based therapeutic interventions to treat post-COVID-19 symptoms (also called "Long-COVID symptoms") have not yet been established, and the treating physicians must rely on conjecture to help patients. Based on its mechanism of action and its efficacy in treating cognitive impairment, as well as its good tolerability, the Ginkgo biloba special extract EGb 761 has been suggested as a remedy to alleviate cognitive post-COVID-19 symptoms. In many studies, EGb 761 has been demonstrated to protect endothelial cells, to have potent anti-inflammatory effects, and to enhance neuroplasticity. CASE REPORT Here, we report for the first time the application of EGb 761 in the therapy of post-COVID-19-related cognitive deficits. Three women and 2 men, aged 26 to 59 years (average age 34.6 years), presented with concentration and attention deficits, cognitive deficiencies, and/or fatigue 9-35 weeks after infection. A daily dose of 2×80 mg of EGb 761 did not cause any detectable adverse effects, and it substantially improved or completely restored cognitive deficits and, when initially present, also other symptoms, such as fatigue and hyposmia, within an observation period of up to 6 months. CONCLUSIONS Our observations support the hypothesis that EGb 761 might be a low-risk treatment option for post-COVID-19 patients with cognitive symptoms. Moreover, we derive recommendations for randomized controlled clinical trials to confirm efficacy in that indication.

Aged rodents have been used as preclinical models of age-associated cognitive decline. Most of those models displayed substantial impairments in learning and memory. The initial, more subtle changes that precede more severe losses in cognitive abilities have not been well characterized. Here, we established a model detecting initial subtle cognitive changes by comparing the performance of moderately aged Oncins France Strain A Sprague Dawley rats with young rats in the Morris water maze (MWM) and the Open Field (OF) test. Both age groups improved their performance during the training period at a similar rate; however, the older rats performed worse in several parameters measured in the MWM. Our results suggest that already at the age of 18-20 months rats show changes in their approach to solve the spatial memory task while their ability to learn is not yet diminished. The disparate spatial information processing of the moderately aged rats provides a novel animal model for early age-related cognitive alterations that could be useful to test the effect of early intervention strategies. Moreover, our results suggest that the sensitivity of cognitive tests in the elderly could be substantially enhanced if they assess both the improvement after several trials, and the strategy used to solve a certain task., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Tinnitus is defined as the perception of sound in the absence of external acoustic stimuli. Frequent comorbidities or associated factors are depression, anxiety, concentration problems, insomnia, resignation, helplessness, headache, bruxism, or social isolation, just to name a few. Although many therapeutic approaches have already been tested with varying success, there still is no cure available for tinnitus. The search for an effective treatment has been hampered by the fact that the mechanisms of tinnitus development are still not fully understood, although several models are available and discussed in this review. Our review will give a brief overview about preclinical models, presenting the heterogeneity of tinnitus sub-types depending on the different inner ear and brain structures involved in tinnitus etiology and pathogenesis. Based on these models we introduce the different target structures and transmitter systems implicated in tinnitus development and provide an extensive overview on preclinical drug-based therapeutic approaches that have been explored in various animal models. As the special extract from Ginkgo biloba leaves EGb 761® has been the most widely tested drug in both non-clinical tinnitus models as well as in clinical trials, a special focus will be given to EGb 761®. The efficacy of terpene lactones, flavone glycosides and proanthocyanidines with their distinct contribution to the overall efficacy profile of the multi-constituent drug EGb 761® will be discussed., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Mutations in the gene encoding leucine-rich repeat kinase 2 ( LRRK2 ), such as the G2019S mutation, are the most common cause of familial Parkinson's disease (PD). The G2019S mutation impairs neurite outgrowth. We hypothesized that those effects could be related to an altered expression of pluripotency genes, which may provide a readout for a screening assay based on LRRK2 function. Here, we show that the G2019S mutation mediates a sustained aberrant upregulation of the transcription factors Nanog and Oct4 that in wild-type are downregulated after differentiation. The aberrant regulation of Nanog can be concentration dependently reversed by LRRK2 tool inhibitors. Building on this knowledge, we developed an assay for the identification and assessment of compounds that inhibit the aberrant pathophysiological activity of mutant LRRK2 . Furthermore, the aberrant neural pluripotency is consistent with Parkinson's pathophysiology and with the epidemiological association between the G2019S genotype and cancer risk.

Many aspects of stress-induced physiological and psychological effects have been characterized in people and animals. However, stress effects on the auditory system are less explored and their mechanisms are not well-understood, in spite of its relevance for a variety of diseases, including tinnitus. To expedite further research of stress-induced changes in the auditory system, here we compare the reactions to stress among Wistar and Lewis rats. The animals were stressed for 24 h, and subsequently we tested the functionality of the outer hair cells (OHCs) using distortion product otoacoustic emissions (DPOAEs) and auditory neurons using evoked auditory brainstem responses (ABR). Lastly, using Western blot, we analyzed the levels of plasticity-related proteins in the inferior colliculus, confirming that the inferior colliculus is involved in the adaptive changes that occur in the auditory system upon stress exposure. Surprisingly, the two strains reacted to stress quite differently: Lewis rats displayed a lowering of their auditory threshold, whereas it was increased in Wistar rats. These functional differences were seen in OHCs of the apical region (low frequencies) and in the auditory neurons (across several frequencies) from day 1 until 2 weeks after the experimental stress ended. Wistar and Lewis rats may thus provide models for auditory threshold increase and decrease, respectively, which can both be observed in different patients in response to stress.

Background: Neuroinflammation is a key factor of Alzheimer's disease (AD) and other neurodegenerative conditions. Microglia are the resident mononuclear immune cells of the central nervous system (CNS). They play an essential role in the maintenance of homeostasis and responses to neuroinflammation. Ginkgo biloba extract EGb 761 is one of the most commonly used natural medicines owing to its established efficacy and remarkable biological activities especially in respect to CNS diseases. However, only few studies have addressed the effects and mechanisms of Ginkgo biloba extract in microglia activation., Methods: We measured the production of pro-inflammatory mediators and cytokines by ELISA and analyzed gene expressions by qRT-PCR and Western Blot in LPS treated cultured primary rat microglia., Results: The Ginkgo biloba extract EGb 761 significantly inhibited the release of prostaglandin E 2 (PGE 2 ) and differentially regulated the levels of pro-inflammatory cytokines. The inhibition of LPS-induced PGE 2 release in primary microglia was partially dependent on reduced protein synthesis of mPGES-1 and the reduction in the activation of cytosolic phospholipase A2 (cPLA2) without altering COX-2 enzymatic activity, inhibitor of kappa B alpha (IkappaBalpha) degradation, and the activation of multiple mitogen activated protein kinases (MAPKs). Altogether, we showed that EGb 761 reduces neuro-inflammatory activation in primary microglial cells by targeting PGE 2 release and cytokines., Conclusion: Ginkgo biloba extract EGb 761 displayed anti-neuroinflammatory activity in LPS-activated primary microglia cells. EGb 761 was able to reduce neuroinflammatory activation by targeting the COX/PGE 2 pathway. This effect might contribute to the established clinical cognitive efficacy in Alzheimer's disease, vascular and mixed dementia., (Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Sortilin was first identified based on its activity as part of intracellular protein sorting machinery. Recently, it was discovered that sortilin also acts as a cell surface receptor for the propeptide form of nerve growth factor (proNGF), progranulin, and neurotensin. The interaction of sortilin to these neurotrophic ligands is linked to diseases of the nervous system that lead to neurodegeneration and neuropathic pain. Blocking of the interaction of sortilin to these ligands may prevent or slow the progress of these nervous system disorders. In vitro screening assays for blocking compounds or peptides are part of the standard set of tools for drug discovery. However, assays for sortilin biology are not readily available to determine if the selected blocking agent inhibits sortilin activity on the surface of cells. We have developed a sortilin specific cell based assay to identify compounds that specifically block interaction between sortilin and proNGF prodomain. The assay system records both the presence of sortilin on the cell surface and the interaction with the pro domain of NGF. Fluorescent images of the sortilin expressing cells are analyzed for the presence of pro domain of NGF. Sortilin-positive and sortilin-negative cells within one well are concomitantly and automatically analyzed. Sortilin-pro domain interaction can be blocked dose dependently by neurotensin and synthetic compounds. The assay will facilitate the discovery of entities interfering with the binding of sortilin to the NGF pro domain. This assay can be modified to screen for inhibitors of the binding of ligands to other complex cell surface receptors.