The role of statins in amyotrophic lateral sclerosis: protective or not?

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons characterized by muscle weakness, muscle twitching, and muscle wasting. ALS is regarded as the third-most frequent neurodegenerative disease, subsequent to Alzheimer's disease (AD) and Parkinson's disease (PD). The World Health Organization (WHO) in 2007 declared that prolonged use of statins may induce development of ALS-like syndrome and may increase ALS risk. Subsequently, different studies have implicated statins in the pathogenesis of ALS. In contrast, results from preclinical and clinical studies highlighted the protective role of statins against ALS neuropathology. Recently, meta-analyses and systematic reviews illustrated no association between long-term use of statins and ALS risk. These findings highlighted controversial points regarding the effects of statins on ALS pathogenesis and risk. The neuroprotective effects of statins against the development and progression of ALS may be mediated by regulating dyslipidemia and inflammatory changes. However, the mechanism for induction of ALS neuropathology by statins may be related to the dysregulation of liver X receptor signaling (LXR) signaling in the motor neurons and reduction of cholesterol, which has a neuroprotective effect against ALS neuropathology. Nevertheless, the exact role of statins on the pathogenesis of ALS was not fully elucidated. Therefore, this narrative review aims to discuss the role of statins in ALS neuropathology.

The potential role of brain renin-angiotensin system in the neuropathology of Parkinson disease: Friend, foe or turncoat?

Parkinson disease (PD) is one of the most common neurodegenerative diseases of the brain. Of note, brain renin-angiotensin system (RAS) is intricate in the PD neuropathology through modulation of oxidative stress, mitochondrial dysfunction and neuroinflammation. Therefore, modulation of brain RAS by angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) may be effective in reducing the risk and PD neuropathology. It has been shown that all components including the peptides and enzymes of the RAS are present in the different brain areas. Brain RAS plays a critical role in the regulation of memory and cognitive function, and in the controlling of central blood pressure. However, exaggerated brain RAS is implicated in the pathogenesis of different neurodegenerative diseases including PD. Two well-known pathways of brain RAS are recognized including; the classical pathway which is mainly mediated by AngII/AT1R has detrimental effects. Conversely, the non-classical pathway which is mostly mediated by ACE2/Ang1-7/MASR and AngII/AT2R has beneficial effects against PD neuropathology. Exaggerated brain RAS affects the viability of dopaminergic neurons. However, the fundamental mechanism of brain RAS in PD neuropathology was not fully elucidated. Consequently, the purpose of this review is to disclose the mechanistic role of RAS in in the pathogenesis of PD. In addition, we try to revise how the ACEIs and ARBs can be developed for therapeutics in PD.

Dysregulation of pancreatic ß-cell autophagy and the risk of type 2 diabetes.

Macroautophagy/autophagy is an essential degradation process that removes abnormal cellular components, maintains homeostasis within cells, and provides nutrition during starvation. Activated autophagy enhances cell survival during stressful conditions, although overactivation of autophagy triggers induction of autophagic cell death. Therefore, early-onset autophagy promotes cell survival whereas late-onset autophagy provokes programmed cell death, which can prevent disease progression. Moreover, autophagy regulates pancreatic ß-cell functions by different mechanisms, although the precise role of autophagy in type 2 diabetes (T2D) is not completely understood. Consequently, this mini-review discusses the protective and harmful roles of autophagy in the pancreatic ß cell and in the pathophysiology of T2D.

The functional and molecular roles of p75 neurotrophin receptor (p75NTR) in epilepsy.

Epilepsy is a chronic neurological disorder manifested by recurring unprovoked seizures resulting from an imbalance in the inhibitory and excitatory neurotransmitters in the brain. The process of epileptogenesis involves a complex interplay between the reduction of inhibitory gamma-aminobutyric acid (GABA) and the enhancement of excitatory glutamate. Pro-BDNF/p75NTR expression is augmented in both glial cells and neurons following epileptic seizures and status epileptics (SE). Over-expression of p75NTR is linked with the pathogenesis of epilepsy, and augmentation of pro-BDNF/p75NTR is implicated in the pathogenesis of epilepsy. However, the precise mechanistic function of p75NTR in epilepsy has not been completely elucidated. Therefore, this review aimed to revise the mechanistic pathway of p75NTR in epilepsy.

Roles of p75 neurotrophin receptor (p75NTR) in epilepsy: Epilepsy is a chronic neurological disorder manifested by recurring unprovoked seizures resulting from an imbalance in the inhibitory and excitatory neurotransmitters in the brain. The process of epileptogenesis involves a complex interplay between the reduction of inhibitory gamma-aminobutyric acid (GABA) and the enhancement of excitatory glutamate. Pro-BDNF/p75NTR expression is augmented in both glial cells and neurons following epileptic seizures and status epileptics (SE). Over-expression of p75NTR is linked with the pathogenesis of epilepsy, and augmentation of pro-BDNF/p75NTR is implicated in the pathogenesis of epilepsy. However, the precise mechanistic function of p75NTR in epilepsy has not been completely elucidated.

Sleep disorders cause Parkinson's disease or the reverse is true: Good GABA good night.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative brain disease due to degeneration of dopaminergic neurons (DNs) presented with motor and non-motor symptoms. PD symptoms are developed in response to the disturbance of diverse neurotransmitters including γ-aminobutyric acid (GABA). GABA has a neuroprotective effect against PD neuropathology by protecting DNs in the substantia nigra pars compacta (SNpc). It has been shown that the degeneration of GABAergic neurons is linked with the degeneration of DNs and the progression of motor and non-motor PD symptoms. GABA neurotransmission is a necessary pathway for normal sleep patterns, thus deregulation of GABAergic neurotransmission in PD could be the potential cause of sleep disorders in PD. AIM: Sleep disorders affect GABA neurotransmission leading to memory and cognitive dysfunction in PD. For example, insomnia and short sleep duration are associated with a reduction of brain GABA levels. Moreover, PD-related disorders including rigidity and nocturia influence sleep patterns leading to fragmented sleep which may also affect PD neuropathology. However, the mechanistic role of GABA in PD neuropathology regarding motor and non-motor symptoms is not fully elucidated. Therefore, this narrative review aims to clarify the mechanistic role of GABA in PD neuropathology mainly in sleep disorders, and how good GABA improves PD. In addition, this review of published articles tries to elucidate how sleep disorders such as insomnia and REM sleep behavior disorder (RBD) affect PD neuropathology and severity. The present review has many limitations including the paucity of prospective studies and most findings are taken from observational and preclinical studies. GABA involvement in the pathogenesis of PD has been recently discussed by recent studies. Therefore, future prospective studies regarding the use of GABA agonists in the management of PD are suggested to observe their distinct effects on motor and non-motor symptoms. CONCLUSION: There is a bidirectional relationship between the pathogenesis of PD and sleep disorders which might be due to GABA deregulation.

Role of ketogenic diet in neurodegenerative diseases focusing on Alzheimer diseases: The guardian angle.

The ketogenic diet (KD) is a low-carbohydrate, adequate protein and high-fat diet. KD is primarily used to treat refractory epilepsy. KD was shown to be effective in treating different neurodegenerative diseases. Alzheimer disease (AD) is the first common neurodegenerative disease in the world characterized by memory and cognitive impairment. However, the underlying mechanism of KD in controlling of AD and other neurodegenerative diseases are not discussed widely. Therefore, this review aims to revise the fundamental mechanism of KD in different neurodegenerative diseases focusing on the AD. KD induces a fasting-like which modulates the central and peripheral metabolism by regulating mitochondrial dysfunction, oxidative stress, inflammation, gut-flora, and autophagy in different neurodegenerative diseases. Different studies highlighted that KD improves AD neuropathology by regulating synaptic neurotransmission and inhibiting of neuroinflammation and oxidative stress. In conclusion, KD improves cognitive function and attenuates the progression of AD neuropathology by reducing oxidative stress, mitochondrial dysfunction, and enhancing neuronal autophagy and brain BDNF.

Therapeutic Potential Effect of Glycogen Synthase Kinase 3 Beta (GSK-3ß) Inhibitors in Parkinson Disease: Exploring an Overlooked Avenue.

Parkinson's disease (PD) is a progressive neurodegenerative disease of the brain due to degeneration of dopaminergic neurons in the substantia nigra (SN). Glycogen synthase kinase 3 beta (GSK-3ß) is implicated in the pathogenesis of PD. Therefore, the purpose of the present review was to revise the mechanistic role of GSK-3ß in PD neuropathology, and how GSK-3ß inhibitors affect PD neuropathology. GSK-3 is a conserved threonine/serine kinase protein that is intricate in the regulation of cellular anabolic and catabolic pathways by modulating glycogen synthase. Over-expression of GSK-3ß is also interconnected with the development of different neurodegenerative diseases. However, the underlying mechanism of GSK-3ß in PD neuropathology is not fully clarified. Over-expression of GSK-3ß induces the development of PD by triggering mitochondrial dysfunction and oxidative stress in the dopaminergic neurons of the SN. NF-κB and NLRP3 inflammasome are activated in response to dysregulated GSK-3ß in PD leading to progressive neuronal injury. Higher expression of GSK-3ß in the early stages of PD neuropathology might contribute to the reduction of neuroprotective brain-derived neurotrophic factor (BDNF). Thus, GSK-3ß inhibitors may be effective in PD by reducing inflammatory and oxidative stress disorders which are associated with degeneration of dopaminergic in the SN.

The classical and non-classical axes of renin-angiotensin system in Parkinson disease: The bright and dark side of the moon.

Parkinson disease (PD) is a common brain neurodegenerative disease due to progressive degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). Of note, the cardio-metabolic disorders such as hypertension are adversely affect PD neuropathology through exaggeration of renin-angiotensin system (RAS). The RAS affects the stability of dopaminergic neurons in the SNpc, and exaggeration of angiotensin II (AngII) is implicated in the development and progression of PD. RAS has two axes classical including angiotensin converting enzyme (ACE)/AngII/AT1R, and the non-classical axis which include ACE2/Ang1-7/Mas receptor, AngIII, AngIV, AT2R, and AT4R. It has been shown that brain RAS is differs from that of systemic RAS that produce specific neuronal effects. As well, there is an association between brain RAS and PD. Therefore, this review aims to revise from published articles the role of brain RAS in the pathogenesis of PD focusing on the non-classical pathway, and how targeting of this axis can modulate PD neuropathology.

New insight on the possible role of statins in Vascular Parkinsonism: A need for presumptive therapy.

Vascular Parkinsonism (VP) is clinical term represents a progressive ischemic changes and subcortical lacunar infarct leading to Parkinsonism mainly in the lower limbs so called lower body Parkinsonism. The VP neuropathology is differed from that of PD neuropathology which rarely associated with basal ganglion lesions. Dopamine transporters are normal in VP but are highly reduced in PD, and dopaminergic agonists had no effective role on VP. The neuropathological mechanisms of VP are related to vascular injury which induces the interruption of the neural connection between basal ganglion and cerebral cortex. Hyperlipidemia and other cardiometabolic risk factors augment VP risk and the related neuropathology. Targeting of these cardiometabolic disorders by lipid-lowering statins may be effective in the management of VP. Therefore, this mini-review aims to clarify the possible role of statins in the management of VP. Statins have neuroprotective effects against different neurodegenerative diseases by anti-inflammatory, antioxidant and antithrombotic effects with enhancement of endothelial function. In conclusion, statins can prevent and treat VP by inhibiting inflammatory and oxidative stress disorders, mitigating of white matter hyperintensities and improving of neuronal signaling pathways. Additional preclinical, clinical trials and prospective studies are warranted in this regard.

Role of brain renin-angiotensin system in depression: A new perspective.

Depression is a mood disorder characterized by abnormal thoughts. The pathophysiology of depression is related to the deficiency of serotonin (5HT), which is derived from tryptophan (Trp). Mitochondrial dysfunction, oxidative stress, and neuroinflammation are involved in the pathogenesis of depression. Notably, the renin-angiotensin system (RAS) is involved in the pathogenesis of depression, and different findings revealed that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may be effective in depression. However, the underlying mechanism for the role of dysregulated brain RAS-induced depression remains speculative. Therefore, this review aimed to revise the conceivable role of ACEIs and ARBs and how these agents ameliorate the pathophysiology of depression. Dysregulation of brain RAS triggers the development and progression of depression through the reduction of brain 5HT and expression of brain-derived neurotrophic factor (BDNF) and the induction of mitochondrial dysfunction, oxidative stress, and neuroinflammation. Therefore, inhibition of central classical RAS by ARBS and ACEIs and activation of non-classical RAS prevent the development of depression by regulating 5HT, BDNF, mitochondrial dysfunction, oxidative stress, and neuroinflammation.

Evaluation and targeting of amyloid precursor protein (APP)/amyloid beta (Aß) axis in amyloidogenic and non-amyloidogenic pathways: A time outside the tunnel.

In Alzheimer disease (AD), amyloid precursor protein (APP) and production of amyloid beta (Aß) which is generated by amyloidogenic pathway is implicated in neurotoxicity and neuronal cell deaths. However, physiological Aß level is essential to improves neuronal survival, attenuates neuronal apoptosis and has neuroprotective effect. In addition, physiological APP level has neurotrophic effect on the central nervous system (CNS). APP has a critical role in the brain growth and development via activation of long-term potentiation (LTP) and acceleration of neurite outgrowth. Moreover, APP is cleaved by α secretase to form a neuroprotective soluble APP alpha (sAPPα) in non-amyloidogenic pathway. Consequently, this mini-review purposes to highlight the possible beneficial role of APP and Aß. In addition, this mini-review discussed the modulation of APP processing and Aß production.

The link between metabolic syndrome and Alzheimer disease: A mutual relationship and long rigorous investigation.

It has been illustrated that metabolic syndrome (MetS) is associated with Alzheimer disease (AD) neuropathology. Components of MetS including central obesity, hypertension, insulin resistance (IR), and dyslipidemia adversely affect the pathogenesis of AD by different mechanisms including activation of renin-angiotensin system (RAS), inflammatory signaling pathways, neuroinflammation, brain IR, mitochondrial dysfunction, and oxidative stress. MetS exacerbates AD neuropathology, and targeting of molecular pathways in MetS by pharmacological approach could a novel therapeutic strategy in the management of AD in high risk group. However, the underlying mechanisms of these pathways in AD neuropathology are not completely clarified. Therefore, this review aims to elucidate the association between MetS and AD regarding the oxidative and inflammatory mechanistic pathways.

The conceivable role of prolactin hormone in Parkinson disease: The same goal but with different ways.

Parkinson disease (PD) is a progressive neurodegenerative disease (NDD) of the brain. It has been reported that prolactin (PRL) hormone plays a differential effect in PD, may be increasing, reduced or unaffected. PRL level is dysregulated in different neurodegenerative disorders including PD. Preclinical and clinical studies pointed out that PRL may has a neuroprotective against PD neuropathology . Though, the mechanistic role of PRL in PD is not fully elucidated. Therefore, the objective of the present review was to clarify the potential role and mechanistic pathway of PRL in PD neuropathology. The present review highlighted that PRL appears to have a neuroprotective effect against PD neuropathology by inhibiting the expression of pro-inflammatory signaling pathways, antioxidant effects and by inhibiting neuroinflammation. Thus, preclinical and clinical studies are warranted in this regard.

Antidepressants and type 2 diabetes: highways to knowns and unknowns.

Type 2 diabetes (T2D) is a metabolic disease caused by the development of insulin resistance (IR), relative insulin deficiency, and hyperglycemia. Hyperglycemia-induced neurochemical dysregulation activates the progression of depression in T2D patients. Therefore, management of depression by antidepressant agents improves glucose homeostasis and insulin sensitivity. However, prolong use of antidepressant drugs may increase the risk for the development of T2D. However, there is strong controversy concerning the use of antidepressant drugs in T2D. Therefore, this review try to elucidate the potential effects of antidepressant drugs in T2D regarding their detrimental and beneficial effects.