Aishwarya Mary Johnson

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta resulting in an irreversible and a debilitating motor dysfunction. Though both genetic and idiopathic factors are implicated in the disease etiology, idiopathic PD comprise the majority of clinical cases and is caused by exposure to environmental toxicants and oxidative stress. Fyn kinase activation has been identified as an early molecular signaling event that primes neuroinflammatory and neurodegenerative events associated with dopaminergic cell death. However, the upstream regulator of Fyn activation remains unidentified. We investigated whether the lipid and tyrosine phosphatase PTEN (Phosphatase and Tensin homolog deleted on chromosome 10) could be the upstream regulator of Fyn activation in PD models as PTEN has been previously reported to contribute to Parkinsonian pathology. Our findings, using bioluminescence resonance energy transfer (BRET) and immunoblotting, indicate for the first time that PTEN is a critical early stress sensor in response to oxidative stress and neurotoxicants in in vitro models of PD. Pharmacological attenuation of PTEN activity rescues dopaminergic neurons from neurotoxicant-induced cytotoxicity by modulating Fyn kinase activation. Our findings also identify PTEN’s novel roles in contributing to mitochondrial dysfunction which contribute to neurodegenerative processes. Interestingly, we found that PTEN positively regulates interleukin-1β (IL-1β) and the transcription of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Taken together, we have identified PTEN as a disease course altering pharmacological target that may be further validated for the development of novel therapeutic strategies targeting PD. Graphical Abstract

Fifth lumbar (L5) nerve injury in rodent produces neuropathic manifestations in the corresponding hind paw. The aim of this study was to investigate the effect of cutaneous injection of resiniferatoxin (RTX), a TRPV1 receptor agonist, in the rat’s hind paw on the neuropathic pain induced by L5 nerve injury. The results showed that intraplantar injection of RTX (0.002%, 100 µL) (1) completely reversed the development of chronic thermal and mechanical hypersensitivity; (2) completely prevented the development of nerve-injury-induced thermal and mechanical hypersensitivity when applied one week earlier; (3) caused downregulation of nociceptive pain markers, including TRPV1, IB4 and CGRP, and upregulation of VIP in the ipsilateral dorsal horn of spinal cord and dorsal root ganglion (DRG) immunohistochemically and a significant reduction in the expression of TRPV1 mRNA and protein in the ipsilateral DRG using Western blot and qRT-PCR techniques; (4) caused downregulation of PGP 9.5- and CGRP-immunoreactivity in the injected skin; (5) produced significant suppression of c-fos expression, as a neuronal activity marker, in the spinal neurons in response to a second intraplantar RTX injection two weeks later. This work identifies the ability of cutaneous injection of RTX to completely alleviate and prevent the development of different types of neuropathic pain in animals and humans.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by a selective degeneration of dopaminergic neurons in the ventral mid-brain of humans called substantia nigra. This results in an irreversible and debilitating motor dysfunction. Though both genetic and idiopathic factors are implicated in the disease etiology, idiopathic PD comprise the majority of clinical cases and is caused due to environmental toxicants and oxidative stress. Activation of Fyn kinase has been implicated to be an early signalling event that primes both neuroinflammatory and neurodegenerative events associated with dopaminergic cell death. Fyn kinase is activated by dephosphorylation at the negatively regulating tyrosine site by tyrosine phosphatases. However, the tyrosine phosphatase that dephosphorylates and activates Fyn kinase is unidentified. One of the tyrosine phosphatases - PTEN (Phosphatase and Tensin homolog deleted on chromosome 10) a lipid and protein tyrosine phosphatase pathological roles in causing Parkinson’s disease has been previously studied in experimental models. We sought to study if PTEN would be the upstream regulator of Fyn activation in PD models. Our findings demonstrate for the first time that PTEN is a very early stress-sensor in response to oxidative stress and neurodegenerative toxicants in in vitro models of PD. Pharmacological inhibition of PTEN attenuates Fyn kinase and rescues dopaminergic neurons from neurotoxicants induced cytotoxicity. Our findings also identify PTEN’s additional and novel roles in contributing to mitochondrial dysfunction and neuroinflammatory pathways, both of which contribute to neurodegenerative processes. Taken together, we have identified PTEN as a disease course altering pharmacological target that may be further validated for the development of novel therapeutic strategies.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the novel coronavirus disease 2019 (COVID-19) pandemic that lacks globally accessible effective antivirals or extensively available vaccines. Numerous clinical trials are exploring the applicability of repurposed monoclonal antibodies (mAbs) targeting cytokines that cause adverse COVID-19-related pathologies, and novel mAbs directly targeting SARS-CoV-2. However, comorbidities and the incidence of cytokine storm (CS)-associated pathological complexities in some COVID-19 patients may limit the clinical use of these drugs. Additionally, CS-targeting mAbs have the potential to cause adverse events that restrict their applicability in patients with comorbidities. Novel mAbs targeting SARS-CoV-2 require pharmacological and toxicological characterization before a marketable product becomes available. The affordability of novel mAbs across the global economic spectrum may seriously limit their accessibility. This review presents a perspective on antibody-based research efforts and their limitations for COVID-19.