Amyloid‐β precursor protein synthesis inhibitors for Alzheimer's disease treatment

Repositioning drugs for traumatic brain injury - N-acetyl cysteine and Phenserine

“…We evaluated the actions of an experimental and reversible anti-acetylcholinesterase (AChE) agent, (−)-phenserine tartrate ((−)-Phen) [ 58 ] in a well-characterized mild concussive model of TBI in mouse [ 59 – 64 ]. Notably, in addition to its anti-AChE activity, (−)-Phen is able to inhibit the synthesis of amyloid precursor protein (APP) and alpha-synuclein (α-syn), proteins of consequence in the pathology of AD and PD, respectively, and of currently increasing relevance to TBI in light of the up regulation of pathways leading to AD and PD in animal models of TBI [ 9 – 12 ] and in light of increased risk for early onset dementia and PD in humans suffering TBI [ 7 , 8 , 65 – 67 ]. In addition, (−)-Phen possesses anti-inflammatory properties [ 68 ], also a phenomenon of significance in TBI [ 69 ], although the majority of anti-inflammatory approaches have failed [ 70 ].…”

“…(−)- (−)-Phen, developed as a drug candidate for AD at the NIA, is a low molecular weight (mw 487.5), (−)- chirally pure, lipophilic (Log D 2.2) orally bio-available agent. The compound was originally developed as an acetyl- cholinesterase selective inhibitor with a high brain delivery [ 71 – 73 ]; importantly it is administered in the form of its tartrate salt to support its required aqueous solubility for pharmacological action [ 9 ]. In this regard, (−)-Phen and three active first-pass hepatic metabolites readily enter brain (approx.…”

“…From a clinical perspective, TBI is one of the most powerful environmental risk factors for development of Alzheimer’s disease (AD). Recent gene expression studies have defined the up-regulation of pathways leading to AD and Parkinson’s disease induced by mild, let alone moderate or severe forms of TBI [ 9 – 12 ]. In light of the lack of any available therapeutic options, it is important to understand the mechanisms that underlie head injury and the neuronal dysfunction and loss that ensue as well as possible therapeutics.…”

“…First, an initial primary damage phase occurs at the moment of insult. This includes contusion and laceration, diffuse axonal injury and intracranial hemorrhage, and results in instantaneous (necrotic) cell death [ 9 , 13 ]. This period is followed by an extended second phase that encompasses cascades of biological processes initiated at the time of injury that may persist over much longer times consequent to ischemia, neuroinflammation, glutamate toxicity, astrocyte reactivity, axonal shearing and apoptosis [ 14 – 17 ].…”

“…This period is followed by an extended second phase that encompasses cascades of biological processes initiated at the time of injury that may persist over much longer times consequent to ischemia, neuroinflammation, glutamate toxicity, astrocyte reactivity, axonal shearing and apoptosis [ 14 – 17 ]. Increasing evidence suggests that secondary brain injury may be reversible; depending on the biological cascades that drive the delayed secondary phase that occurs following TBI and how quickly and effectively these can be interrupted or mitigated [ 9 , 18 ]. These cascades involve neuroinflammation, oxidative stress, generation of reactive oxygen species, inhibition of neurogenesis, apoptosis, loss of cholinergic circuits, and glutamate excitotoxicity.…”