Potential Mechanisms Underlying COVID-19-Mediated Central and Peripheral Demyelination: Roles of the RAAS and ADAM-17.

Demyelination is among the most conspicuous neurological sequelae of SARS-CoV-2 infection (COVID-19) in both the central (CNS) and peripheral (PNS) nervous systems. Several hypotheses have been proposed to explain the mechanisms underlying demyelination in COVID-19. However, none have considered the SARS-CoV-2's effects on the renin-angiotensin-aldosterone system (RAAS). Therefore, our objective in this review is to evaluate how RAAS imbalance, caused by direct and indirect effects of SARS-CoV-2 infection, could contribute to myelin loss in the PNS and CNS. In the PNS, we propose that demyelination transpires from two significant changes induced by SARS-CoV-2 infection, which include upregulation of ADAM-17 and induction of lymphopenia. Whereas, in the CNS, demyelination could result from RAAS imbalance triggering two alterations: (1) a decrease in angiotensin type II receptor (AT2R) activity, responsible for restraining defense cells' action on myelin; (2) upregulation of ADAM-17 activity, leading to impaired maturation of oligodendrocytes and myelin formation. Thus, we hypothesize that increased ADAM-17 activity and decreased AT2R activity play roles in SARS-CoV-2 infection-mediated demyelination in the CNS.

Effects of cocaine, nicotine, and marijuana exposure in Drosophila Melanogaster development: A systematic review and meta-analysis.

Abuse-related drug usage is a public health issue. Drosophila melanogaster has been used as an animal model to study the biological effects of these psychoactive substances in preclinical studies. Our objective in this review is to evaluate the adverse effects produced by cocaine, nicotine, and marijuana during the development of D. melanogaster. We searched experimental studies in which D. melanogaster was exposed to these three psychoactive drugs in seven online databases up to January 2023. Two reviewers independently extracted the data. Fifty-one studies met eligibility criteria and were included in the data extraction: nicotine (n = 26), cocaine (n = 20), and marijuana (n = 5). Fifteen studies were eligible for meta-analysis. Low doses (∼0.6 mM) of nicotine increased locomotor activity in fruit flies, while high doses (≥3 mM) led to a decrease. Similarly, exposure to cocaine increased locomotor activity, resulting in decreased climbing response in D. melanogaster. Studies with exposure to marijuana did not present a profile for our meta-analysis. However, this drug has been less associated with locomotor changes, but alterations in body weight and fat content and changes in cardiac function. Our analyses have shown that fruit flies exposed to drugs of abuse during different developmental stages, such as larvae and adults, exhibit molecular, morphological, behavioral, and survival changes that are dependent on the dosage. These phenotypes resemble the adverse effects of psychoactive substances in clinical medicine.

N-Formyl-Methionyl-Leucyl-Phenylalanine Plays a Neuroprotective and Anticonvulsant Role in Status Epilepticus Model.

Status epilepticus (SE) is described as continuous and self-sustaining seizures, which triggers hippocampal neurodegeneration, inflammation, and gliosis. N-formyl peptide receptor (FPR) has been associated with inflammatory process. N-formyl-methionyl-leucyl-phenylalanine (fMLP) peptide plays an anti-inflammatory role, mediated by the activation of G-protein-coupled FPR. Here, we evaluated the influence of fMLP peptides on the behavior of limbic seizures, memory consolidation, and hippocampal neurodegeneration process. Male Wistar rats (Rattus norvegicus) received microinjections of pilocarpine in hippocampus (H-PILO, 1.2 mg/µL, 1 µL) followed by fMLP (1 mg/mL, 1 µL) or vehicle (VEH, saline 0.9%, 1 µL). During the 90 min of SE, epileptic seizures were analyzed according to the Racine's Scale. After 24 h of SE, memory impairment was assessed by the inhibitory avoidance test and the neurodegeneration process was evaluated in hippocampal areas. There was no change in latency and number of wet dog shake (WDS) after administration of fMLP. However, our results showed that the intrahippocampal infusion of fMLP reduced the severity of seizures, as well as the number of limbic seizures. In addition, fMLP infusion protected memory dysfunction followed by SE. Finally, the intrahippocampal administration of fMLP attenuated the process of neurodegeneration in both hippocampi. Taken together, our data suggest a new insight into the functional role of fMLP peptides, with important implications for their potential use as a therapeutic agent for the treatment of brain disorders, such as epilepsy. Schematic drawing on the neuroprotective and anticonvulsant role of fMLP during status epilepticus. Initially, a cannula was implanted in hippocampus and pilocarpine/saline was administered into the hippocampus followed by fMLP/saline (A-C). fMLP reduced seizure severity and neuronal death in the hippocampus, as well as protecting against memory deficit (D).

Maternal crack cocaine use in rats leads to depressive- and anxiety-like behavior, memory impairment, and increased seizure susceptibility in the offspring.

Crack users suffer the effects of cocaine present in the drug and the action of other active compounds from its pyrolysis. An emergent fact is an increase in the number of pregnant crack cocaine users. Studies suggest that crack cocaine and its metabolites cross the placenta, promoting premature birth, fever, irritability, sweating, and seizures in the early months of life. In children, the effects of crack cocaine have been associated with cognitive deficits, difficulty in verbalization, aggressiveness, and depression, besides enhancing the susceptibility to epileptic seizures, including status epilepticus (SE) in adulthood. Therefore, we investigated the effect of maternal exposure to smoke crack cocaine on several behavioral parameters in the offspring during adulthood. A series of behavioral tests and intrahippocampal pilocarpine (H-PILO) microinjection at sub-convulsive and convulsive doses in a rat model demonstrated that exposure to crack cocaine during the embryonic period leads to anxiogenic-like behavior and long-term memory impairment in both genders and promotes depressive-like behavior in the female. Besides, crack cocaine offspring exposed to a sub-convulsive H-PILO dose showed higher susceptibility to SE, increased seizure frequency, and neurodegeneration, while animals that received a convulsive dose of H-PILO displayed no alteration in SE severity. Taken together, our data suggest that crack cocaine exposure during the gestational period leads to an increased predilection for anxiety and depression, long-term memory deficits, and reduction in the threshold for developing epileptic seizures associated with neuronal death, which predispose crack cocaine babies to develop neuropsychological disorders.

Ultra-Endurance Associated With Moderate Exercise in Rats Induces Cerebellar Oxidative Stress and Impairs Reactive GFAP Isoform Profile.

Ultra-endurance (UE) race has been associated with brain metabolic changes, but it is still unknown which regions are vulnerable. This study investigated whether high-volume training in rodents, even under moderate intensity, can induce cerebellar oxidative and inflammatory status. Forty-five adult rats were divided into six groups according to a training period, followed or not by an exhaustion test (ET) that simulated UE: control (C), control + ET (C-ET), moderate-volume (MV) training and MV-ET, high-volume training (HV) and HV-ET. The training period was 30 (MV) and 90 (HV) min/day, 5 times/week for 3 months as a continuous running on a treadmill at a maximum velocity of 12 m/min. After 24 h, the ET was performed at 50% maximum velocities up to the animals refused to run, and then serum lactate levels were evaluated. Serum and cerebellar homogenates were obtained 24 h after ET. Serum creatine kinase (CK), lactate dehydrogenase (LDH), and corticosterone levels were assessed. Lipid peroxidation (LP), nitric oxide (NO), Interleukin 1ß (IL-1ß), and GFAP proteins, reduced and oxidized glutathione (GSH and GSSG) levels, superoxide dismutase (SOD) and catalase (CAT) activities were quantified in the cerebellum. Serum lactate concentrations were lower in MV-ET (∼20%) and HV-ET (∼40%) compared to the C-ET group. CK and corticosterone levels were increased more than ∼ twofold by HV training compared to control. ET increased CK levels in MV-ET vs. MV group (P = 0.026). HV induced higher LP levels (∼40%), but an additive effect of ET was only seen in the MV-ET group (P = 0.02). SOD activity was higher in all trained groups vs. C and C-ET (P < 0.05). CAT activity, however, was intensified only in the MV group (P < 0.02). The 50 kDa GFAP levels were enhanced in C-ET and MV-ET vs. respective controls, while 42 kDa (∼40%) and 39 kDa (∼26%) isoform levels were reduced. In the HV-ET group, the 50 KDa isoform amount was reduced ∼40-60% compared to the other groups and the 39 KDa isoform, increased sevenfold. LDH levels, GSH/GSSG ratio, and NO production were not modified. ET elevated IL-1ß levels in the CT and MV groups. Data shows that cerebellar resilience to oxidative damage may be maintained under moderate-volume training, but it is reduced by UE running. High-volume training per se provoked systemic metabolic changes, cerebellar lipid peroxidation, and unbalanced enzymatic antioxidant resource. UE after high-volume training modified the GFAP isoform profile suggesting impaired astrocyte reactivity in the cerebellum.