From the Gut to the Brain: Is Microbiota a New Paradigm in Parkinson's Disease Treatment?

Parkinson's disease (PD) is recognized as the second most prevalent primary chronic neurodegenerative disorder of the central nervous system. Clinically, PD is characterized as a movement disorder, exhibiting an incidence and mortality rate that is increasing faster than any other neurological condition. In recent years, there has been a growing interest concerning the role of the gut microbiota in the etiology and pathophysiology of PD. The establishment of a brain-gut microbiota axis is now real, with evidence denoting a bidirectional communication between the brain and the gut microbiota through metabolic, immune, neuronal, and endocrine mechanisms and pathways. Among these, the vagus nerve represents the most direct form of communication between the brain and the gut. Given the potential interactions between bacteria and drugs, it has been observed that the therapies for PD can have an impact on the composition of the microbiota. Therefore, in the scope of the present review, we will discuss the current understanding of gut microbiota on PD and whether this may be a new paradigm for treating this devastating disease.

Glial-restricted precursors stimulate endogenous cytogenesis and effectively recover emotional deficits in a model of cytogenesis ablation.

Adult cytogenesis, the continuous generation of newly-born neurons (neurogenesis) and glial cells (gliogenesis) throughout life, is highly impaired in several neuropsychiatric disorders, such as Major Depressive Disorder (MDD), impacting negatively on cognitive and emotional domains. Despite playing a critical role in brain homeostasis, the importance of gliogenesis has been overlooked, both in healthy and diseased states. To examine the role of newly formed glia, we transplanted Glial Restricted Precursors (GRPs) into the adult hippocampal dentate gyrus (DG), or injected their secreted factors (secretome), into a previously validated transgenic GFAP-tk rat line, in which cytogenesis is transiently compromised. We explored the long-term effects of both treatments on physiological and behavioral outcomes. Grafted GRPs reversed anxiety-like deficits and demonstrated an antidepressant-like effect, while the secretome promoted recovery of only anxiety-like behavior. Furthermore, GRPs elicited a recovery of neurogenic and gliogenic levels in the ventral DG, highlighting the unique involvement of these cells in the regulation of brain cytogenesis. Both GRPs and their secretome induced significant alterations in the DG proteome, directly influencing proteins and pathways related to cytogenesis, regulation of neural plasticity and neuronal development. With this work, we demonstrate a valuable and specific contribution of glial progenitors to normalizing gliogenic levels, rescuing neurogenesis and, importantly, promoting recovery of emotional deficits characteristic of disorders such as MDD.

N-Acetylcysteine Treatment May Compensate Motor Impairments through Dopaminergic Transmission Modulation in a Striatal 6-Hydroxydopamine Parkinson's Disease Rat Model.

Preventing degeneration and the loss of dopaminergic neurons (DAn) in the brain while mitigating motor symptoms remains a challenge in Parkinson's Disease (PD) treatment development. In light of this, developing or repositioning potential disease-modifying approaches is imperative to achieve meaningful translational gains in PD research. Under this concept, N-acetylcysteine (NAC) has revealed promising perspectives in preserving the dopaminergic system capability and modulating PD mechanisms. Although NAC has been shown to act as an antioxidant and (neuro)protector of the brain, it has yet to be acknowledged how this repurposed drug can improve motor symptomatology and provide disease-modifying properties in PD. Therefore, in the present work, we assessed the impact of NAC on motor and histological deficits in a striatal 6-hydroxydopamine (6-OHDA) rat model of PD. The results revealed that NAC enhanced DAn viability, as we found that it could restore dopamine transporter (DAT) levels compared to the untreated 6-OHDA group. Such findings were positively correlated with a significant amelioration in the motor outcomes of the 6-OHDA-treated animals, demonstrating that NAC may, somehow, be a modulator of PD degenerative mechanisms. Overall, we postulated a proof-of-concept milestone concerning the therapeutic application of NAC. Nevertheless, it is extremely important to understand the complexity of this drug and how its therapeutical properties interact with the cellular and molecular PD mechanisms.

StressMatic: A Novel Automated System to Induce Depressive- and Anxiety-like Phenotype in Rats.

Major depressive disorder (MDD) is a multidimensional psychiatric disorder that is estimated to affect around 350 million people worldwide. Generating valid and effective animal models of depression is critical and has been challenging for neuroscience researchers. For preclinical studies, models based on stress exposure, such as unpredictable chronic mild stress (uCMS), are amongst the most reliable and used, despite presenting concerns related to the standardization of protocols and time consumption for operators. To overcome these issues, we developed an automated system to expose rodents to a standard uCMS protocol. Here, we compared manual (uCMS) and automated (auCMS) stress-exposure protocols. The data shows that the impact of the uCMS exposure by both methods was similar in terms of behavioral (cognition, mood, and anxiety) and physiological (cell proliferation and endocrine variations) measurements. Given the advantages of time and standardization, this automated method represents a step forward in this field of preclinical research.

Neuroinflammation and Parkinson's Disease-From Neurodegeneration to Therapeutic Opportunities.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide. Clinically, it is characterized by a progressive degeneration of dopaminergic neurons (DAn), resulting in severe motor complications. Preclinical and clinical studies have indicated that neuroinflammation can play a role in PD pathophysiology, being associated with its onset and progression. Nevertheless, several key points concerning the neuroinflammatory process in PD remain to be answered. Bearing this in mind, in the present review, we cover the impact of neuroinflammation on PD by exploring the role of inflammatory cells (i.e., microglia and astrocytes) and the interconnections between the brain and the peripheral system. Furthermore, we discuss both the innate and adaptive immune responses regarding PD pathology and explore the gut-brain axis communication and its influence on the progression of the disease.

Suppression of adult cytogenesis in the rat brain leads to sex-differentiated disruption of the HPA axis activity.

OBJECTIVES: The action of stress hormones, mainly glucocorticoids, starts and coordinates the systemic response to stressful events. The HPA axis activity is predicated on information processing and modulation by upstream centres, such as the hippocampus where adult-born neurons (hABN) have been reported to be an important component in the processing and integration of new information. Still, it remains unclear whether and how hABN regulates HPA axis activity and CORT production, particularly when considering sex differences. MATERIALS AND METHODS: Using both sexes of a transgenic rat model of cytogenesis ablation (GFAP-Tk rat model), we examined the endocrinological and behavioural effects of disrupting the generation of new astrocytes and neurons within the hippocampal dentate gyrus (DG). RESULTS: Our results show that GFAP-Tk male rats present a heightened acute stress response. In contrast, GFAP-Tk female rats have increased corticosterone secretion at nadir, a heightened, yet delayed, response to an acute stress stimulus, accompanied by neuronal hypertrophy in the basal lateral amygdala and increased expression of the glucocorticoid receptors in the ventral DG. CONCLUSIONS: Our results reveal that hABN regulation of the HPA axis response is sex-differentiated.

Hippocampal cytogenesis abrogation impairs inter-regional communication between the hippocampus and prefrontal cortex and promotes the time-dependent manifestation of emotional and cognitive deficits.

Impaired ability to generate new cells in the adult brain has been linked to deficits in multiple emotional and cognitive behavioral domains. However, the mechanisms by which abrogation of adult neural stem cells (NSCs) impacts on brain function remains controversial. We used a transgenic rat line, the GFAP-Tk, to selectively eliminate NSCs and assess repercussions on different behavioral domains. To assess the functional importance of newborn cells in specific developmental stages, two parallel experimental timeframes were adopted: a short- and a long-term timeline, 1 and 4 weeks after the abrogation protocol, respectively. We conducted in vivo electrophysiology to assess the effects of cytogenesis abrogation on the functional properties of the hippocampus and prefrontal cortex, and on their intercommunication. Adult brain cytogenesis abrogation promoted a time-specific installation of behavioral deficits. While the lack of newborn immature hippocampal neuronal and glial cells elicited a behavioral phenotype restricted to hyperanxiety and cognitive rigidity, specific abrogation of mature new neuronal and glial cells promoted the long-term manifestation of a more complex behavioral profile encompassing alterations in anxiety and hedonic behaviors, along with deficits in multiple cognitive modalities. More so, abrogation of 4 to 7-week-old cells resulted in impaired electrophysiological synchrony of neural theta oscillations between the dorsal hippocampus and the medial prefrontal cortex, which are likely to contribute to the described long-term cognitive alterations. Hence, this work provides insight on how newborn neurons and astrocytes display different functional roles throughout different maturation stages, and establishes common ground to reconcile contrasting results that have marked this field.

Adult brain cytogenesis in the context of mood disorders: From neurogenesis to the emergent role of gliogenesis.

Psychiatric disorders severely impact patients' lives. Motivational, cognitive and emotional deficits are the most common symptoms observed in these patients and no effective treatment is still available, either due to the adverse side effects or the low rate of efficacy of currently available drugs. Neurogenesis recovery has been one important focus in the treatment of psychiatric disorders, which undeniably contributes to the therapeutic action of antidepressants. However, glial plasticity is emerging as a new strategy to explore the deficits observed in mood disorders and the efficacy of therapeutic interventions. Thus, it is crucial to understand the mechanisms behind glio- and neurogenesis to better define treatments and preventive therapies, once adult cytogenesis is of pivotal importance to cognitive and emotional components of behavior, both in healthy and pathological contexts, including in psychiatric disorders. Here, we review the concepts and history of neuro- and gliogenesis, providing as well a reflection on the functional importance of cytogenesis in the context of disease.

Glial restricted precursor cells in central nervous system disorders: Current applications and future perspectives.

The crosstalk between glial cells and neurons represents an exceptional feature for maintaining the normal function of the central nervous system (CNS). Increasing evidence has revealed the importance of glial progenitor cells in adult neurogenesis, reestablishment of cellular pools, neuroregeneration, and axonal (re)myelination. Several types of glial progenitors have been described, as well as their potentialities for recovering the CNS from certain traumas or pathologies. Among these precursors, glial-restricted precursor cells (GRPs) are considered the earliest glial progenitors and exhibit tripotency for both Type I/II astrocytes and oligodendrocytes. GRPs have been derived from embryos and embryonic stem cells in animal models and have maintained their capacity for self-renewal. Despite the relatively limited knowledge regarding the isolation, characterization, and function of these progenitors, GRPs are promising candidates for transplantation therapy and reestablishment/repair of CNS functions in neurodegenerative and neuropsychiatric disorders, as well as in traumatic injuries. Herein, we review the definition, isolation, characterization and potentialities of GRPs as cell-based therapies in different neurological conditions. We briefly discuss the implications of using GRPs in CNS regenerative medicine and their possible application in a clinical setting. MAIN POINTS: GRPs are progenitors present in the CNS with differentiation potential restricted to the glial lineage. These cells have been employed in the treatment of a myriad of neurodegenerative and traumatic pathologies, accompanied by promising results, herein reviewed.

Combination of a Gellan Gum-Based Hydrogel With Cell Therapy for the Treatment of Cervical Spinal Cord Injury.

Cervical spinal cord trauma represents more than half of the spinal cord injury (SCI) cases worldwide. Respiratory compromise, as well as severe limb motor deficits, are among the main consequences of cervical lesions. In the present work, a Gellan Gum (GG)-based hydrogel modified with GRGDS peptide, together with adipose tissue-derived stem/stromal cells (ASCs) and olfactory ensheathing cells (OECs), was used as a therapeutic strategy after a C2 hemisection SCI in rats. Hydrogel or cells alone, and a group without treatment, were also tested. Four weeks after injury, compound muscle action potentials (CMAPs) were performed to assess functional phrenic motor neuron (PhMN) innervation of the diaphragm; no differences were observed amongst groups, confirming that the PhMN pool located between C3 and C5 was not affected by the C2 injury or by the treatments. In the same line, the vast majority of diaphragmatic neuromuscular junctions remained intact. Five weeks post-injury, inspiratory bursting of the affected ipsilateral hemidiaphragm was evaluated through EMG recordings of dorsal, medial and ventral subregions of the muscle. All treatments significantly increased EMG amplitude at the ventral portion in comparison to untreated animals, but only the combinatorial group presented increased EMG amplitude at the medial portion of the hemidiaphragm. No differences were observed in forelimb motor function, neither in markers for axonal regrowth (neuronal tracers), astrogliosis (GFAP) and inflammatory cells (CD68). Moreover, using Von Frey testing of mechanical allodynia, it was possible to find a significant effect of the group combining hydrogel and cells on hypersensitivity; rats with a SCI displayed an increased response of the contralateral forelimb to a normally innocuous mechanical stimulus, but after treatment with the combinatorial therapy this behavior was reverted almost to the levels of uninjured controls. These results suggest that our therapeutic approach may have beneficial effects on both diaphragmatic recovery and sensory function.