Restoration Of Neuronal Function Research Articles

Revolutionizing Neurological Disorder Treatment: Integrating Innovations in Pharmaceutical Interventions and Advanced Therapeutic Technologies.

Neurological disorders impose a significant burden on individuals, leading to disabilities and a reduced quality of life. However, recent years have witnessed remarkable advancements in pharmaceutical interventions aimed at treating these disorders. This review article aims to provide an overview of the latest innovations and breakthroughs in neurological disorder treatment, with a specific focus on key therapeutic areas such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and stroke. This review explores emerging trends in drug development, including the identification of novel therapeutic targets, the development of innovative drug delivery systems, and the application of personalized medicine approaches. Furthermore, it highlights the integration of advanced therapeutic technologies such as gene therapy, optogenetics, and neurostimulation techniques. These technologies hold promise for precise modulation of neural circuits, restoration of neuronal function, and even disease modification. While these advancements offer hopeful prospects for more effective and tailored treatments, challenges such as the need for improved diagnostic tools, identification of new targets for intervention, and optimization of drug delivery methods remain. By addressing these challenges and continuing to invest in research and collaboration, we can revolutionize the treatment of neurological disorders and significantly enhance the lives of those affected by these conditions.

Development of a novel glucose‐dendrimer based therapeutic targeting hyperexcitable neurons in neurological disorders

AbstractNeuronal hyperexcitability and excitotoxicity lies at the core of debilitating brain disorders such as epilepsy and traumatic brain injury, culminating in neuronal death and compromised brain function. Overcoming this challenge requires a unique approach that selectively restores normal neuronal activity and rescues neurons from impending damage. However, delivering drugs selectively to hyperexcitable neurons has been a challenge, even upon local administration. Here, we demonstrate the remarkable ability of a novel, scalable, generation‐two glucose‐dendrimer (GD2) made primarily of glucose and ethylene glycol building blocks, to specifically target hyperexcitable neurons in primary culture, ex vivo acute brain slices, and in vivo mouse models of acute seizures. Pharmacology experiments in ex vivo brain slices suggest GD2 uptake in neurons is mediated through glucose transporters (GLUT and SGLT). Inspired by these findings, we conjugated GD2 with a potent anti‐epileptic drug, valproic acid (GD2–VPA), for efficacy studies in the pilocarpine‐mouse model of seizure. When delivered intranasally, GD2–VPA significantly decreased the seizure‐severity. In summary, our findings demonstrate the unique selectivity of glucose dendrimers in targeting hyperexcitable neurons, even upon intranasal delivery, laying the foundation for neuron‐specific therapies for the precise protection and restoration of neuronal function, for targeted neuroprotection.

Functional Restoration following Global Cerebral Ischemia in Juvenile Mice following Inhibition of Transient Receptor Potential M2 (TRPM2) Ion Channels.

Hippocampal cell death and cognitive dysfunction are common following global cerebral ischemia across all ages, including children. Most research has focused on preventing neuronal death. Restoration of neuronal function after cell death is an alternative approach (neurorestoration). We previously identified transient receptor potential M2 (TRPM2) ion channels as a potential target for acute neuroprotection and delayed neurorestoration in an adult CA/CPR mouse model. Cardiac arrest/cardiopulmonary resuscitation (CA/CPR) in juvenile (p20-25) mice was used to investigate the role of ion TRPM2 channels in neuroprotection and ischemia-induced synaptic dysfunction in the developing brain. Our novel TRPM2 inhibitor, tatM2NX, did not confer protection against CA1 pyramidal cell death but attenuated synaptic plasticity (long-term plasticity (LTP)) deficits in both sexes. Further, in vivo administration of tatM2NX two weeks after CA/CPR reduced LTP impairments and restored memory function. These data provide evidence that pharmacological synaptic restoration of the surviving hippocampal network can occur independent of neuroprotection via inhibition of TRPM2 channels, providing a novel strategy to improve cognitive recovery in children following cerebral ischemia. Importantly, these data underscore the importance of age-appropriate models in disease research.

Edaravone attenuates cadmium-induced toxicity by inhibiting oxidative stress and inflammation in ICR mice

The neurotoxicity caused by cadmium (Cd) is well known in humans and experimental animals. However, there is no effective treatment for its toxicity. In this study, we established Cd toxicity models in cultured cells or mice to investigate the detoxification effect of edaravone (Eda). We found that Eda protected GL261 cells from Cd toxicity and prevented the loss of cell viability. In Cd-exposed mice, liver, kidney and testicular damage, as well as cognitive dysfunction were observed. Oxidative stress and inflammatory responses, such as decreased SOD and CAT, increased LDH and MDA, and abnormal changes in the inflammatory factors TNF-α, IL-1β, IL-6 and IL-10 were detected in serum and brain tissue. Eda protected mice from Cd-induced toxicity and abrogated oxidative stress and inflammatory responses. Also, Eda prevented inflammatory activation of microglia and astrocytes and was accompanied by restoration of the neuronal marker protein MAP2, indicating restoration of neuronal function. In addition, the BDNF-TrkB/Akt and Notch/HES-1 signaling axes were involved in the response of Eda to the elimination of Cd toxicity. In conclusion, Eda does contribute to the clearance of Cd-induced toxicity.

Microglia CREB-Phosphorylation Mediates Amyloid-β-Induced Neuronal Toxicity.

Extracellular accumulation of amyloid-β (Aβ) forming senile plaques is one of the hallmark pathologies in Alzheimer's disease (AD), while the mechanisms underlying the neuronal toxic effect of Aβ are not fully understood. Here, we found that intracerebroventricular infusion of the aged Aβ42 in mice only induces memory deficit at 24 h but not at 7 days. Interestingly, a remarkably increased CREB (cAMP response element-binding protein) Ser133-phosphorylation (pS133-CREB) with microglial activation was detected at 24 h but not at 7 days after Aβ infusion. Aβ treatment for 24 h increased pS133-CREB level in microglia of the hippocampal non-granular cell layers with remarkably decreased pS133-CREB immunoreactivity in neurons of the hippocampal granular cell layers, including CA1, CA3, and DG subsets. Inhibition of microglia activation by minocycline or CREB phosphorylation by H89, an inhibitor of protein kinase A (PKA), abolished Aβ-induced microglia CREB hyperphosphorylation with restoration of neuronal function and attenuation of inflammatory response, i.e., reduced levels of interleukin-6 (IL6) and pCREB binding of matrix metalloproteinase-9 (MMP9) DNA. Finally, treatment of the primary hippocampal neurons with Aβ-potentiated microglia media decreased neuronal GluN1 and GluA2 levels, while simultaneous inhibition of PKA restored the levels. These novel findings reveal that intracerebroventricular infusion of Aβ only induces transient memory deficit in mice and the molecular mechanisms involve a stimulated microglial CREB phosphorylation.

Expression profiles of cholesterol metabolism-related genes are altered during development of experimental autoimmune encephalomyelitis in the rat spinal cord

Increased evidence suggests that dysregulation of cholesterol metabolism may be a key event contributing to progression of multiple sclerosis (MS). Using an experimental autoimmune encephalomyelitis (EAE) model of MS we revealed specific changes in the mRNA and protein expression of key molecules involved in the maintaining of cholesterol homeostasis in the rat spinal cord: 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR), apolipoprotein E (ApoE) and cholesterol 24-hydroxylase (CYP46A1) during the course of disease. The presence of myelin lipid debris was seen only at the peak of EAE in demyelination loci being efficiently removed during the recovery period. Since CYP46A1 is responsible for removal of cholesterol excess, we performed a detailed profiling of CYP46A1 expression and revealed regional and temporal specificities in its distribution. Double immunofluorescence staining demonstrated CYP46A1 localization with neurons, infiltrated macrophages, microglia and astrocytes in the areas of demyelination, suggesting that these cells play a role in cholesterol turnover in EAE. We propose that alterations in the regulation of cholesterol metabolism at the onset and peak of EAE may add to the progression of disease, while during the recovery period may have beneficial effects contributing to the regeneration of myelin sheath and restoration of neuronal function.

Neural Probes for Chronic Applications.

Developed over approximately half a century, neural probe technology is now a mature technology in terms of its fabrication technology and serves as a practical alternative to the traditional microwires for extracellular recording. Through extensive exploration of fabrication methods, structural shapes, materials, and stimulation functionalities, neural probes are now denser, more functional and reliable. Thus, applications of neural probes are not limited to extracellular recording, brain-machine interface, and deep brain stimulation, but also include a wide range of new applications such as brain mapping, restoration of neuronal functions, and investigation of brain disorders. However, the biggest limitation of the current neural probe technology is chronic reliability; neural probes that record with high fidelity in acute settings often fail to function reliably in chronic settings. While chronic viability is imperative for both clinical uses and animal experiments, achieving one is a major technological challenge due to the chronic foreign body response to the implant. Thus, this review aims to outline the factors that potentially affect chronic recording in chronological order of implantation, summarize the methods proposed to minimize each factor, and provide a performance comparison of the neural probes developed for chronic applications.

Polyethylene glycol-fused allografts produce rapid behavioral recovery after ablation of sciatic nerve segments.

Restoration of neuronal functions by outgrowths regenerating at ∼1 mm/day from the proximal stumps of severed peripheral nerves takes many weeks or months, if it occurs at all, especially after ablation of nerve segments. Distal segments of severed axons typically degenerate in 1-3 days. This study shows that Wallerian degeneration can be prevented or retarded, and lost behavioral function can be restored, following ablation of 0.5-1-cm segments of rat sciatic nerves in host animals. This is achieved by using 0.8-1.1-cm microsutured donor allografts treated with bioengineered solutions varying in ionic and polyethylene glycol (PEG) concentrations (modified PEG-fusion procedure), being careful not to stretch any portion of donor or host sciatic nerves. The data show that PEG fusion permanently restores axonal continuity within minutes, as initially assessed by action potential conduction and intracellular diffusion of dye. Behavioral functions mediated by the sciatic nerve are largely restored within 2-4 weeks, as measured by the sciatic functional index. Increased restoration of sciatic behavioral functions after ablating 0.5-1-cm segments is associated with greater numbers of viable myelinated axons within and distal to PEG-fused allografts. Many such viable myelinated axons are almost certainly spared from Wallerian degeneration by PEG fusion. PEG fusion of donor allografts may produce a paradigm shift in the treatment of peripheral nerve injuries.

Promise of Neurorestoration and Mitochondrial Biogenesis in Parkinson's Disease with Multi Target Drugs: An Alternative to Stem Cell Therapy

There is an unmet need in progressive neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. The present therapeutics for these diseases at best is symptomatic and is not able to delay disease or possess disease modifying activity. Thus an approach to drug design should be made to slow or halt progressive course of a neurological disorder by interfering with a disease-specific pathogenetic process. This would entail the ability of the drug to protect neurons by blocking the common pathway for neuronal injury and cell death and the ability to promote regeneration of neurons and restoration of neuronal function. We have now developed a number of multi target drugs which possess neuroprotective, and neurorestorative activity as well as being able to active PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α), SIRT1 (NAD-dependent deacetylase protein) and NTF (mitochondrial transcription factor) that are intimately associated with mitochondrial biogenesis.

Restoring Neuronal Function After Stroke by Cell Replacement

A major challenge to effective treatment after stroke is the restoration of neuronal function. In recent years, cell-based therapies for stroke have been explored in experimental animal models, and the results have suggested behavioral improvements. However, the anatomic targets of a cell-based stroke therapy and the relationship of cell grafts to post stroke reorganization are poorly understood, which results in difficulties defining strategies for neuronal substitution. Given that stroke causes a variety of secondary changes at locations beyond the infarct lesion, overcoming these difficulties is even more important. We describe which brain structures and cell types are candidates for substitution and how new neuronal functionality could be implemented in a damaged brain by capitalizing on current concepts of post stroke plasticity.

Ectopic Norrin Induces Growth of Ocular Capillaries and Restores Normal Retinal Angiogenesis in Norrie Disease Mutant Mice

Norrie disease is an X-linked retinal dysplasia that presents with congenital blindness, sensorineural deafness, and mental retardation. Norrin, the protein product of the Norrie disease gene (NDP), is a secreted protein of unknown biochemical function. Norrie disease (Ndp(y/-)) mutant mice that are deficient in norrin develop blindness, show a distinct failure in retinal angiogenesis, and completely lack the deep capillary layers of the retina. We show here that the transgenic expression of ectopic norrin under control of a lens-specific promoter restores the formation of a normal retinal vascular network in Ndp(y/-) mutant mice. The improvement in structure correlates with restoration of neuronal function in the retina. In addition, lenses of transgenic mice with ectopic expression of norrin show significantly more capillaries in the hyaloid vasculature that surrounds the lens during development. In vitro, lenses of transgenic mice in coculture with microvascular endothelial cells induce proliferation of the cells. Transgenic mice with ectopic expression of norrin show more bromodeoxyuridine-labeled retinal progenitor cells at embryonic day 14.5 and thicker retinas at postnatal life than wild-type littermates, indicating a putative direct neurotrophic effect of norrin. These data provide direct evidence that norrin induces growth of ocular capillaries and that pharmacologic modulation of norrin might be used for treatment of the vascular abnormalities associated with Norrie disease or other vascular disorders of the retina.