Systematic Review of the Therapeutic Role of Apoptotic Inhibitors in Neurodegeneration and Their Potential Use in Schizophrenia

Abstract

Schizophrenia (SZ) is a deleterious brain disorder affecting cognition, emotion and reality perception. The most widely accepted neurochemical-hypothesis is the imbalance of neurotransmitter-systems. Depleted GABAergic-inhibitory function might produce a regionally-located dopaminergic and glutamatergic-storm in the brain. The dopaminergic-release may underlie the positive psychotic-symptoms while the glutamatergic-release could prompt the primary negative symptoms/cognitive deficits. This may occur due to excessive synaptic-pruning during the neurodevelopmental stages of adolescence/early adulthood. Thus, although SZ is not a neurodegenerative disease, it has been suggested that exaggerated dendritic-apoptosis could explain the limited neuroprogression around its onset. This apoptotic nature of SZ highlights the potential therapeutic action of anti-apoptotic drugs, especially at prodromal stages. If dysregulation of apoptotic mechanisms underlies the molecular basis of SZ, then anti-apoptotic molecules could be a prodromal therapeutic option to halt or prevent SZ. In fact, risk alleles related in apoptotic genes have been recently associated to SZ and shared molecular apoptotic changes are common in the main neurodegenerative disorders and SZ. PRISMA-guidelines were considered. Anti-apoptotic drugs are commonly applied in classic neurodegenerative disorders with promising results. Despite both the apoptotic-hallmarks of SZ and the widespread use of anti-apoptotic targets in neurodegeneration, there is a strikingly scarce number of studies investigating anti-apoptotic approaches in SZ. We analyzed the anti-apoptotic approaches conducted in neurodegeneration and the potential applications of such anti-apoptotic therapies as a promising novel therapeutic strategy, especially during early stages.

Keywords: apoptosis; apoptotic inhibitors; schizophrenia; systematic review; therapy.

Figure 1

Neuronal features in SZ. Cortical pyramidal neurons from subjects with schizophrenia exhibit smaller soma volume, decreased spine density, decreased dendritic length and decreased terminals.

Figure 2

Two prototypical apoptotic pathways (extrinsic and intrinsic) initiated by separate events converge at a common place to execute apoptosis. Main associations of these apoptotic pathways to the neurodegenerative disorders AD, PD, HD as well as SZ are indicated. Death receptor pathways triggered by binding of death receptors by their ligands (tumor necrosis factor (TNF, FasL) that results in receptor clustering and recruitment of adaptor proteins, leading to the activation of initiator caspase-8. The intrinsic pathway responds to a variety of cellular stress signals that act on mitochondria to cause leakage of pro-apoptotic effectors like cytochrome c and apoptosis-inducing factor (AIF). Cytochrome c binds to Apaf-1 in the presence of ATP to form the “apoptosome”, which subsequently recruits and activates initiator pro-caspase-9. AIF translocates to the nucleus to cause high molecular weight DNA fragmentation in a caspase-independent manner. Both pathways activate effector caspases-3 and -7. Endoplasmic reticulum stress causes the activation and release of caspase-12, leading to apoptotic cell death. AIF, apoptosis-inducing factor; AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; Apaf, apoptotic protease activating factor; Bak, Bcl-2 homologous antagonist killer; Bax, Bcl-2 associated X protein; Bcl, B-cell lymphoma; Bid, BH3 interacting domain death agonist; Casp, caspase; CytC, cytochrome c; FADD, Fas-associated-death-domain protein; FAS, cysteine-rich transmembrane protein CD95; HD, Huntington’s disease; PD, Parkinson’s disease; SZ, schizophrenia; tBid, truncated Bid; TNF, tumor necrosis factor.

Figure 3

Different mechanisms by which the anti-apoptotic molecules herein discussed could target apoptosis, directly or indirectly through excitotoxicity, mitochondrial alterations and derived oxidative stress and inflammation.