Alzheimer's disease: Molecular aspects and treatment opportunities using herbal drugs.

Alzheimer's disease (AD), also called senile dementia, is the most common neurological disorder. Around 50 million people, mostly of advanced age, are suffering from dementia worldwide and this is expected to reach 100-130 million between 2040 and 2050. AD is characterized by impaired glutamatergic and cholinergic neurotransmission, which is associated with clinical and pathological symptoms. AD is characterized clinically by loss of cognition and memory impairment and pathologically by senile plaques formed by Amyloid ß deposits or neurofibrillary tangles (NFT) consisting of aggregated tau proteins. Amyloid ß deposits are responsible for glutamatergic dysfunction that develops NMDA dependent Ca2+ influx into postsynaptic neurons generating slow excitotoxicity process leading to oxidative stress and finally impaired cognition and neuronal loss. Amyloid decreases acetylcholine release, synthesis and neuronal transport. The decreased levels of neurotransmitter acetylcholine, neuronal loss, tau aggregation, amyloid ß plaques, increased oxidative stress, neuroinflammation, bio-metal dyshomeostasis, autophagy, cell cycle dysregulation, mitochondrial dysfunction, and endoplasmic reticulum dysfunction are the factors responsible for the pathogenesis of AD. Acetylcholinesterase, NMDA, Glutamate, BACE1, 5HT6, and RAGE (Receptors for Advanced Glycation End products) are receptors targeted in treatment of AD. The FDA approved acetylcholinesterase inhibitors Donepezil, Galantamine and Rivastigmine and N-methyl-D-aspartate antagonist Memantine provide symptomatic relief. Different therapies such as amyloid ß therapies, tau-based therapies, neurotransmitter-based therapies, autophagy-based therapies, multi-target therapeutic strategies, and gene therapy modify the natural course of the disease. Herbal and food intake is also important as preventive strategy and recently focus has also been placed on herbal drugs for treatment. This review focuses on the molecular aspects, pathogenesis and recent studies that signifies the potential of medicinal plants and their extracts or chemical constituents for the treatment of degenerative symptoms related to AD.

Interaction of morphine tolerance with pentylenetetrazole-induced seizure threshold in mice: The role of NMDA-receptor/NO pathway.

N-methyl-d-aspartate receptor (NMDA-R)/nitric oxide (NO) pathway is involved in the intensification of the analgesic effect of opioids and the reduction of the intensity of opioids tolerance and dependence. In the current study, we investigated the involvement of NMDA-R/NO pathway in chronic morphine-treated mice in both the development of tolerance to the analgesic effect of morphine and in pentylenetetrazole (PTZ)-induced seizure threshold. Chronic treatment with morphine (30 mg/kg) exhibited increased seizure resistance in morphine-induced tolerant mice. The development of morphine tolerance was withdrawn when used concomitantly with NOS inhibitors and NMDA-R antagonist, suggesting that the development of tolerance to the anticonvulsant effect of morphine (30 mg/kg) is mediated through the NMDA-R/NO pathway. A dose-dependent biphasic seizure modulation of morphine was demonstrated in the acute treatment with morphine; acute treatment at a dose of 0.5 mg/kg shows the anticonvulsant effect and at a dose of 30 mg/kg shows proconvulsant effect. However, a different pattern was observed in the mice treated chronically with morphine: they demonstrated tolerance in the tail-flick test; five consecutive days of chronic treatment with a high dose of morphine (30 mg/kg) showed anticonvulsant effect while a low dose of morphine (0.5 mg/kg) showed a proconvulsant effect. The anticonvulsant effect of morphine was inhibited completely by the concomitant administration of NO synthase (NOS) inhibitors including nonspecific NOS inhibitor (L-NAME, 10 mg/kg), inducible NOS inhibitor (aminoguanidine, 50 mg/kg), and neuronal NOS inhibitor (7-nitroindazole (7-NI), 15 mg/kg) for five consecutive days. Besides, five days injection of NMDA-R antagonist (MK-801, 0.05 mg/kg) significantly inhibited the anticonvulsant effect of morphine on the PTZ-induced clonic seizures. The results revealed that chronic treatment with morphine leads to the development of tolerance in mice, which in turn may cause an anticonvulsant effect in a high dose of morphine via the NMDA-R/NO pathway.

Cannabinoids inhibit neurodegeneration in models of multiple sclerosis.

Multiple sclerosis is increasingly being recognized as a neurodegenerative disease that is triggered by inflammatory attack of the CNS. As yet there is no satisfactory treatment. Using experimental allergic encephalo myelitis (EAE), an animal model of multiple sclerosis, we demonstrate that the cannabinoid system is neuroprotective during EAE. Mice deficient in the cannabinoid receptor CB1 tolerate inflammatory and excitotoxic insults poorly and develop substantial neurodegeneration following immune attack in EAE. In addition, exogenous CB1 agonists can provide significant neuroprotection from the consequences of inflammatory CNS disease in an experimental allergic uveitis model. Therefore, in addition to symptom management, cannabis may also slow the neurodegenerative processes that ultimately lead to chronic disability in multiple sclerosis and probably other diseases.

Treatment of acute cerebral infarction.

This review focuses on the recent advances in the management of acute ischemic stroke. We highlight the best current treatment, as proposed by different authors, as well as future lines of treatment.

[The effect of N-methyl-D,L-aspartic acid on the nociceptive reaction of mice]. / Vliianie N-metil-D,L-asparaginovoi kisloty na notsitseptivnuiu reaktsiiu u myshei.

Intraperitoneal NMDLA was pharmacologically studied in mice for effects by using the hot-plate test. The agent given in a subconvulsive dose of 50 mg/kg showed a biphasic action: 5 minutes after administration there was hyperalgesia (Phase I) followed by hypoalgesia (Phase II) 15 minutes later. The effects of phencyclidine, ketamine, morphine, naloxone, bromocriptine and isradipine on NMDLA's analgetic action were also examined. Bearing in mind the fact that the action of NMDLA is decreased by isradipine in Phase I and by receptor-acting agents in Phase II it is suggested that there is a great difference in the patterns of the two phases of the analgetic action of NMDLA systemically used.

A mouse model of focal cerebral ischemia for screening neuroprotective drug effects.

The aim of the present study was to investigate if the infarct area on the brain surface after middle cerebral artery (MCA) occlusion in the mouse is representative for the infarct volume and if this determination of brain injury can be used for screening neuroprotective drug effects. Cerebral infarction was induced by coagulating electrically the stem of the left MCA. After 48 hr, the brains were perfused with carbon black and the unstained infarct area was determined by means of an image analyzing system. The infarct volume was determined by calculating the infarct area on coronal slices and the distance between succeeding slices. The correlation between the area and the volume of infarction was significant (r = 0.81; p less than 0.001). N-methyl-D-aspartate (NMDA) antagonists, calcium antagonists, 5-hydroxytryptamine-1A (5-HT-1A) agonists, radical scavengers, and various drugs were investigated in the mouse model of MCA occlusion. Drugs were usually applicated before ischemia. The drugs that were found to be neuroprotective in the mouse model revealed similar effects in rat models of focal or global cerebral ischemia. These findings show that the presented mouse model with its simple technique of measuring the infarct size is suitable for screening purposes.