Publication: Management of Mitochondrial Oxidative Stress and Neurogenesis Using Bioengineered Nanomedicine Platform
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2024-12-19
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Indian Institute of Technology, Jodhpur
Abstract
This thesis entitled “Management of Mitochondrial Oxidative Stress and Neurogenesis using Bioengineered Nanomedicine Platform” talks about the development of various therapeutics for the treatment of oxidative stress in the central nervous system (CNS) and peripheral nervous system (PNS). The complex pathophysiology of traumatic brain injury (TBI) is a major obstacle, as it includes the central nervous system's (CNS) limited regenerative capacity and an overabundance of reactive oxygen species (ROS). Another challenge is the blood-brain barrier (BBB), which limits the ability to distribute therapeutic medicines to areas that are inflammatory. To address these difficulties, we developed a new approach to treatment using polydopamine (PDA)-coated mesoporous silicon nanoparticles (PDA-AMSNs) to transport a neurochemical modulator (NCM), a possible inhibitor of glycogen synthase kinase-3β (GSK- 3β). A multifunctional therapeutic matrix was created by integrating these nanoparticles with a PANAP hydrogel, which is known for its neuroprotective properties. We created a logic AND gate circuit with PDA-AMSNs and NCM as inputs and neuroprotection as output by injecting this composite system, PDA-AMSN-D, into a cryogenic brain injury (CBI) model. The results highlighted the system's potential for TBI management by demonstrating significant therapeutic efficacy, which included a reduction in infarct volume, enhancement of neurogenesis, restoration of BBB integrity, and improved neurological recovery. This thesis also talks about the design and development of novel mitochondria targeting gallic acid-derived small-molecule drugs for the alleviation of oxidative stress in LPS-induced neuroinflammation. The Overproduction of reactive oxygen species (ROS) by mitochondria, which are essential for cellular homeostasis and energetics, can cause oxidative stress. Neuroinflammation and neurodegeneration are significantly associated with mitochondrial dysfunction. In response to these concerns, we created Mito-TBA, an antioxidant that targets mitochondria and is based on gallic acid and the mitochondriotropic triphenylphosphonium (TPP) cation. Significant anti-inflammatory and antioxidative effects were shown by this new chemical, Mito-TBA-3. In vitro studies demonstrated that Mito-TBA-3 protects neurones derived from PC-12 by inhibiting mitoautophagy, attenuating the activation of lipopolysaccharide-induced toll-like receptor 4 (TLR-4), and activating the Nrf-2/ARE pathway. In a rat model of neuroinflammation caused by LPS, Mito-TBA-3 restored memory loss, reduced depressive symptoms, prevented further inflammation, and lowered levels of proinflammatory cytokines. One possible treatment possibility for neurodegenerative illnesses related to mitochondrial oxidative stress is this chemical, which outperformed aspirin, a commonly used NSAID. Debilitating neuropathies and functional deficits can result from peripheral nerve injuries, especially those that impact the sciatic nerve. Further, this thesis talks about the development of novel peptide-derived scaffolds for nerve regeneration on PNS. For nerve restoration to be successful, it is necessary to precisely align the fascicles so that the nerve sprouts and Büngner bands can reattach. Although autogenous nerve grafting is still highly recommended, it does have certain drawbacks, such as donor site morbidity and inadequate repair efficacy. There is a lack of therapeutic potential in current tissue-engineered nerve scaffolds due to their absence of electrical conductivity, fibre alignment, and components of the extracellular matrix (ECM). A nanofibrous ECMmimicking self-assembling peptide hydrogel, including neuroregenerative motifs (NAP and NAV) and a self-assembling motif (K2(SL)6K2) was devised to address these challenges. Important for directing stem cell orientation and encouraging neurite outgrowth, this hydrogel displayed topographical patterns on a nanoscale. Using morphological and histological investigations, functional assessments, and gastrocnemius muscle reinnervation, the hydrogel enabled structural healing and functional recovery within two weeks in a rat model of sciatic nerve injury. These results demonstrate that hydrogel may be a viable therapeutic option for repairing peripheral nerves. Overall, this thesis gives a glimpse where combining these three treatment modalities highlights the need for new ways to deal with central nervous system trauma, neuroinflammation, and peripheral nerve injury. Each approach takes advantage of ideas from bioinspired design to provide specific, efficient therapies for nerve and neurological disorders. They open the door to a new age of precision medicine and give patients with diseases that were thought to be incurable a glimmer of hope.
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Garg, Shubham (2019).Management of Mitochondrial Oxidative Stress and Neurogenesis Using Bioengineered Nanomedicine Platform (Doctor's thesis).Indian Institute of Technology, Jodhpur