Touqeer Ahmed

Inhibitory effect of curcuminoids on acetylcholinesterase activity and attenuation of scopolamine-induced amnesia may explain medicinal use of turmeric in Alzheimer's disease

Curcuminoids (a mixture of curcumin, bisdemethoxycurcumin and demethoxycurcumin) share vital pharmacological properties possessed by turmeric, a well known curry spice, considered useful in Alzheimers disease (AD). The aim of this study was to evaluate if curcuminoids possess acetylcholinesterase (AChE) inhibitory and memory enhancing activities. The in-vitro and ex-vivo models of AChE inhibitory activity were used along with Morris water maze test to study the effect on memory in rats. Curcuminoids inhibited AChE in the in-vitro assay with IC(50) value of 19.67, bisdemethoxycurcumin 16.84, demethoxycurcumin 33.14 and curcumin 67.69 microM. In the ex-vivo AChE assay, curcuminoids and its individual components except curcumin showed dose-dependent (3-10 mg/kg) inhibition in frontal cortex and hippocampus. When studied for their effect on memory at a fixed dose (10 mg/kg), all compounds showed significant (p<0.001) and comparable effect in scopolamine-induced amnesia. These data indicate that curcuminoids and all individual components except curcumin possess pronounced AChE inhibitory activity. Curcumin was relatively weak in the in-vitro assay and without effect in the ex-vivo AChE model, while equally effective in memory enhancing effect, suggestive of additional mechanism(s) involved. Thus curcuminoids mixture might possess better therapeutic profile than curcumin for its medicinal use in AD.

Curcuminoids enhance memory in an amyloid-infused rat model of Alzheimer's disease

Alzheimers disease (AD) is a neurodegenerative disease. There are a limited number of therapeutic options available for the treatment of AD. Curcuminoids (a mixture of bisdemethoxycurcumin, demethoxycurcumin and curcumin) is the main chemical constituent found in turmeric, a well known curry spice, having potential in the treatment of AD. The objective of this study was to investigate the effects of curcuminoid mixture and individual constituents on spatial learning and memory in an amyloid-beta (Abeta) peptide-infused rat model of AD and on the expression of PSD-95, synaptophysin and camkIV. Curcuminoid mixture showed a memory-enhancing effect in rats displaying AD-like neuronal loss only at 30 mg/kg, whereas individual components were effective at 3-30 mg/kg. A shorter duration treatment with test compounds showed that the curcuminoid mixture and bisdemethoxycurcumin increased PSD-95 expression in the hippocampus at 3-30 mg/kg, with maximum effect at a lower dose (3 mg/kg) with respective values of 470.5 and 587.9%. However, after a longer duration treatment, two other compounds (demethoxycurcumin and curcumin) also increased PSD-95 to 331.7 and 226.2% respectively at 30 mg/kg. When studied for their effect on synaptophysin in the hippocampus after the longer duration treatment, the curcuminoid mixture and all three individual constituents increased synaptophysin expression. Of these, demethoxycurcumin was the most effective showing a 350.1% increase (P<0.01) at 30 mg/kg compared to the neurotoxin group. When studied for their effect on camkIV expression after longer treatment in the hippocampus, only demethoxycurcumin at 30 mg/kg increased levels to 421.2%. These compounds salvaged PSD-95, synaptophysin and camkIV expression levels in the hippocampus in the rat AD model, which suggests multiple target sites with the potential of curcuminoids in spatial memory enhancing and disease modifying in AD.

Quercetin and the mitochondria: A mechanistic view.

Quercetin is an important flavonoid that is ubiquitously present in the diet in a variety of fruits and vegetables. It has been traditionally viewed as a potent antioxidant and anti-inflammatory molecule. However, recent studies have suggested that quercetin may exert its beneficial effects independent of its free radical-scavenging properties. Attention has been placed on the effect of quercetin on an array of mitochondrial processes. Quercetin is now recognized as a phytochemical that can modulate pathways associated with mitochondrial biogenesis, mitochondrial membrane potential, oxidative respiration and ATP anabolism, intra-mitochondrial redox status, and subsequently, mitochondria-induced apoptosis. The present review evaluates recent evidence on the ability of quercetin to interact with the abovementioned pathways, and critically analyses how, such interactions can exert protection against mitochondrial damage in response to toxicity induced by several exogenously and endogenously-produced cellular stressors, and oxidative stress in particular.

Therapeutic Potential of Turmeric in Alzheimer's Disease: Curcumin or Curcuminoids?

Alzheimers disease (AD) is the most common form of dementia. There is limited choice in modern therapeutics, and drugs available have limited success with multiple side effects in addition to high cost. Hence, newer and alternate treatment options are being explored for effective and safer therapeutic targets to address AD. Turmeric possesses multiple medicinal uses including treatment for AD. Curcuminoids, a mixture of curcumin, demethoxycurcumin, and bisdemethoxycurcumin, are vital constituents of turmeric. It is generally believed that curcumin is the most important constituent of the curcuminoid mixture that contributes to the pharmacological profile of parent curcuminoid mixture or turmeric. A careful literature study reveals that the other two constituents of the curcuminoid mixture also contribute significantly to the effectiveness of curcuminoids in AD. Therefore, it is emphasized in this review that each component of the curcuminoid mixture plays a distinct role in making curcuminoid mixture useful in AD, and hence, the curcuminoid mixture represents turmeric in its medicinal value better than curcumin alone. The progress in understanding the disease etiology demands a multiple‐site‐targeted therapy, and the curcuminoid mixture of all components, each with different merits, makes this mixture more promising in combating the challenging disease. Copyright

Ginsenoside Rb1 as a neuroprotective agent: A review

Ginsenosides represent the major bioactive components of ginseng. These triterpenoid saponins have been shown to exert numerous beneficial effects on the human body. Recent evidences suggest that ginsenosides may be useful for the management and treatment of several diseases of the central nervous system (CNS). In particular, numerous in vitro and in vivo models have shown that ginsenosides can modulate numerous pharmacological effects on the brain, including attenuation of excitotoxicity, oxidative stress and neuroinflammation, maintenance of neurotransmitter balance, anti-apoptotic effects, and mitochondrial stabilization effects. Regulations of these pathophysiological mechanisms have been shown to improve cognitive function and protect the brain against several neurodegenerative diseases. This review will critically address the pharmacological effects and mechanisms of action of ginsenosides in the CNS, and particularly those associated with therapeutic efficacies in Parkinsons disease, Alzheimers disease, Huntingtons disease, and traumatic brain injury, and ischemia.

A comparative study of curcuminoids to measure their effect on inflammatory and apoptotic gene expression in an Aβ plus ibotenic acid-infused rat model of Alzheimer's disease

Alzheimers disease (AD) is a neurodegenerative disorder, which depicts features of chronic inflammatory conditions resulting in cellular death and has limited therapeutic options. We aimed to explore the effect of a curcuminoid mixture and its individual components on inflammatory and apoptotic genes expression in AD using an Aβ+ibotenic acid-infused rat model. After 5 days of treatment with demethoxycurcumin, hippocampal IL-1β levels were decreased to 118.54 ± 47.48 and 136.67 ± 31.96% respectively at 30 and 10mg/kg, compared with the amyloid treated group (373.99 ± 15.28%). After 5 days of treatment, the curcuminoid mixture and demethoxycurcumin effectively decreased GFAP levels in the hippocampus. When studied for their effect on apoptotic genes expression, the curcuminoid mixture and bisdemethoxycurcumin effectively decreased caspase-3 level in the hippocampus after 20 days of treatment, where bisdemethoxycurcumin showed a maximal rescuing effect (92.35 ± 3.07%) at 3mg/kg. The curcuminoid mixture at 30 mg/kg decreased hippocampal FasL level to 70.56 ± 3.36% after 5 days of treatment and 19.01 ± 2.03% after 20 days. In the case of Fas receptor levels, demethoxycurcumin decreased levels after 5 days of treatment with all three doses showing a maximal effect (189.76 ± 15.01%) at 10mg/kg. Each compound was effective after 20 days in reducing Fas receptor levels in the hippocampus. This study revealed the important effect of curcuminoids on genes expression, showing that, each component of the curcuminoid mixture distinctly affects gene expression, thus highlighting the therapeutic potential of curcuminoids in AD.

Muscarinic, Ca++ antagonist and specific butyrylcholinesterase inhibitory activity of dried ginger extract might explain its use in dementia

Ginger rhizome (Zingiber officinale) has been used for centuries to treat dementia in South Asia. This study was undertaken to possibly justify its use. A 70% aqueous/methanolic extract of dried ginger (Zo.Cr) was used. Zo.Cr tested positive for the presence of terpenoids, flavonoids, secondary amines, phenols, alkaloids and saponins. When tested on isolated rat stomach fundus, Zo.Cr showed a spasmogenic effect (0.03–5.00 mg mL−1); it relaxed the tissue at concentrations ≥5 mg mL−1. The stimulant effect was resistant to blockade by hexamethonium and methysergide, but sensitive to atropine, indicating activity via muscarinic receptors. In atropinized (0.1 μM) preparations, Zo.Cr (0.3–3.0 mg mL−1) relaxed high K+ (80 mm)‐induced contractions, indicating Ca++ antagonism in addition to the muscarinic effect. This possible Ca++ antagonist activity was investigated in Ca++‐free conditions, with the inhibitory effect of the extract tested against contractions induced by externally administered Ca++. Zo.Cr (0.1–0.3 mg mL−1), similar to verapamil (0.03–0.10 μm), shifted the contractions induced by externally administered Ca++ to the right, thus suggesting an inhibitory interaction between Zo.Cr and voltage‐operated Ca++ channels. Zo.Cr (0.1–3.0 μg mL−1) also potentiated acetylcholine peak responses in stomach fundus, similar to physostigmine, a cholinesterase inhibitor. Zo.Cr, in an in‐vitro assay, showed specific inhibition of butyrylcholinesterase (BuChE) rather than acetylcholinesterase enzyme. Different pure compounds of ginger also showed spasmolytic activity in stomach fundus, with 6‐gingerol being the most potent. 6‐Gingerol also showed a specific anti‐BuChE effect. This study shows a unique combination of muscarinic, possible Ca++ antagonist and BuChE inhibitory activities of dried ginger, indicating its benefit in dementia, including Alzheimers disease.

Resveratrol and Alzheimer's Disease: Mechanistic Insights.

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly and is characterized by progressive cognitive and memory deficits. The pathological hallmarks of AD include extracellular senile plaques and intracellular neurofibrillary tangles. Although several mechanisms have been used to explain the underlying pathogenesis of AD, current treatment regimens remain inadequate. The neuroprotective effects of the polyphenolic stilbene resveratrol (3,5,4′-trihydroxy-trans-stilbene) have been investigated in several in vitro and in vivo models of AD. The current review discusses the multiple potential mechanisms of action of resveratrol on the pathobiology of AD. Moreover, due to the limited pharmacokinetic parameters of resveratrol, multiple strategies aimed at increasing the bioavailability of resveratrol have also been addressed.

Berberine and neurodegeneration: A review of literature

The excessive production of reactive oxygen species in nervous tissues is considered one of the major risk factors of neurodegenerative diseases. During the last two decades, much attention has been paid to the antioxidant and anti-inflammatory activity of natural products and compounds isolated from natural products which are often characterized by high efficacy and low adverse effects. Berberine is an isoquinoline alkaloid, widely present in different medicinal herbs, especially in the genus Berberis. It is mainly used as antidiarrhoeal, antibacterial, antifungal, and antiprotozoal agent. However, current research has focused on its beneficial role in neurodegenerative diseases, mainly due to its powerful antioxidant effect. The therapeutic potential of Berberine in different neurodegenerative diseases such as Alzheimer, Parkinson and Huntington disease has been brought to evidence by numerous studies. However, a limited number of reviews focus on the beneficial role of Berberine against neurodegeneration. The main objective of this review is to discuss the role of oxidative stress in neurodegeneration and the potential role of antioxidant compounds, in particular Berberine which is analyzed in its chemical structure, source, bioavailability, therapeutic potential, with special attention to its mechanism of action at a molecular level.

Bidirectional modulation of fear extinction by mediodorsal thalamic firing in mice

The mediodorsal thalamic nucleus has been implicated in the control of memory processes. However, the underlying neural mechanism remains unclear. Here we provide evidence for bidirectional modulation of fear extinction by the mediodorsal thalamic nucleus. Mice with a knockout or mediodorsal thalamic nucleus–specific knockdown of phospholipase C β4 exhibited impaired fear extinction. Mutant mediodorsal thalamic nucleus neurons in slices showed enhanced burst firing accompanied by increased T-type Ca2+ currents; blocking of T channels in vivo rescued the fear extinction. Tetrode recordings in freely moving mice revealed that, during extinction, the single-spike (tonic) frequency of mediodorsal thalamic nucleus neurons increased in wild-type mice, but was static in mutant mice. Furthermore, tonic-evoking microstimulations of the mediodorsal thalamic nucleus, contemporaneous with the extinction tones, rescued fear extinction in mutant mice and facilitated it in wild-type mice. In contrast, burst-evoking microstimulation suppressed extinction in wild-type mice, mimicking the mutation. These results suggest that the firing mode of the mediodorsal thalamic nucleus is critical for the modulation of fear extinction.