Cell Death Pathways: a Novel Therapeutic Approach for Neuroscientists

Abstract

In the first part, the following mechanisms involved in different forms of cell death are considered, with a view to identifying potential therapeutic targets: tumour necrosis factor receptors (TNFRs) and their engagement by tumour necrosis factor-alpha (TNF-α); poly [ADP-ribose] polymerase (PARP)-1 cleavage; the apoptosis signalling kinase (ASK)-c-Jun N-terminal kinase (JNK) axis; lysosomal permeability; activation of programmed necrotic cell death; oxidative stress, caspase-3 inhibition and parthanatos; activation of inflammasomes by reactive oxygen species and the development of pyroptosis; oxidative stress, calcium dyshomeostasis and iron in the development of lysosomal-mediated necrosis and lysosomal membrane permeability; and oxidative stress, lipid peroxidation, iron dyshomeostasis and ferroptosis. In the second part, there is a consideration of the role of lethal and sub-lethal activation of these pathways in the pathogenesis and pathophysiology of neurodegenerative and neuroprogressive disorders, with particular reference to the TNF-α-TNFR signalling axis; dysregulation of ASK-1-JNK signalling; prolonged or chronic PARP-1 activation; the role of pyroptosis and chronic inflammasome activation; and the roles of lysosomal permeabilisation, necroptosis and ferroptosis. Finally, it is suggested that, in addition to targeting oxidative stress and inflammatory processes generally, neuropsychiatric disorders may respond to therapeutic targeting of TNF-α, PARP-1, the Nod-like receptor NLRP3 inflammasome and the necrosomal molecular switch receptor-interacting protein kinase-3, since their widespread activation can drive and/or exacerbate peripheral inflammation and neuroinflammation even in the absence of cell death. To this end, the use is proposed of a combination of the tetracycline derivative minocycline and N-acetylcysteine as adjunctive treatment for a range of neuropsychiatric disorders.

Role of Lipid Peroxidation Process in Neurodegenerative Disorders

“…These factors alter the cellular and molecular events [98,99]. The anatomy of microvascular system is affecting by the above factors and it raising the oxidative stress environment along with DNA damage, ATP depletion and activation of ferroptosis [100]. The symptoms of neuropathy are the development of autotomy (self-amputation of figures); allodynia (triggering of a pain response from stimuli, but it does not provoke pain in normal condition); hyperalgesia (extreme reaction of painful stimuli); and numbness (unusual prickling sensation).…”

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

“…These findings, allied to those discussed above, may well be important from the perspective of AD pathogenesis as the association between peripherally increased PICs and TREM-2 and increased AD risk and/or severity could be explained by the initiation and/or exacerbation of microglial activation, either as a result of high peripheral PIC levels and/or the egress of activated Th1 and/or Th17 cells into the CNS. Readers interested in the details of the mechanisms involved are referred to these reviews by Morris and colleagues [138] [139]. The pathological consequences of microglial activation and dysfunction and the putative role of these glial cells in the pathogenesis and pathophysiology of AD are discussed below.…”

“…Moreover, acetylcholinesterase (AChE), an enzyme responsible for ACh hydrolysis in the synaptic cleft, is also prone to inhibition in such an environment [250,251]. Furthermore, there is a considerable body of evidence indicating that cholinergic neurones are highly susceptible to apoptotic or necrotic death in an environment of excessive nitrosative and oxidative stress [252,253] via mechanisms detailed in a recent paper by Morris and fellow workers [139]. Readers interested in a detailed consideration of cholinergic neurotransmission and the role of the molecular players described above in the context of AD are invited to consult an excellent review by Ferreira-Vieira and fellow workers [248].…”

“…There, the non-degraded proteins become a potential new source of reactive species, further damaging the lysosomal membrane [318]. This oxidative damage to lysosomal lipid membranes can be exacerbated by high levels of iron seen in AD patients, which increase the sensitivity of these membranes to oxidative damage to the point of inducing apoptotic or necrotic cell death resulting from lysosomal rupture and release of toxic hydroxylases, calpains and redox-active iron into the cytoplasm [139]. There is a growing appreciation that the role of redox-active iron and iron dyshomeostasis as a driver of neuropathology in AD may be pivotal in AD both as a source of increasing oxidative stress, via hydroxyl production through the Fenton reaction, and in the development of amyloid-and tau-related pathology.…”

Citronellol Induces Necroptosis of Human Lung Cancer Cells via TNF-α Pathway and Reactive Oxygen Species Accumulation

“…Another marker of apoptosis is the proteolytic cleavage of poly (ADP-ribose) polymerase (PARP), a nuclear enzyme involved in DNA repair, DNA stability, and transcriptional regulation. PARP is proteolytically inactivated during apoptosis (15)(16)(17), but is activated during necroptosis because of inhibition of caspase 8 (18)(19)(20). Activated complexes I, II can increase calcium and calpain, respectively, leading to lipid peroxidation and activation of cathepsin B/D which is released into the cytoplasm to induce necroptosis (21).…”