dihydropyridines and Nervous-System-Diseases

This mini review is devoted to the design and pharmacological studies of novel atypical 1,4-dihydropyridine (DHP) derivatives which differ to a great extent from the traditional DHPs either by lack of neuronal calcium channel blocking activity and/or inability to protect mitochondrial processes. About 100 new DHP derivatives were screened and the mostly active were selected for detailed studies. The compounds of the series of the amino acid ("free" plus "crypto")-containing DHPs and lipophilic di-cyclic DHPs demonstrated long-lasting neuroprotective and/or memory-enhancing action, particularly at low doses (0.005-0.05mg/kg) in different neurodeficiency rat or mice models, and exerted neurotransmitter-modulating effects. The studies have shown an ability of these atypical DHPs to normalize the expression of neuronal proteins, which participate in the regulation of neurotransmission (particularly of the GABAergic system) and synaptic plasticity that has been impaired in animal models, including Alzheimer's disease transgenic mice. The obtained results indicate that the tested DHP compounds can be considered as candidate molecules either for their further chemical modifications or for the more detailed studies to identify cell targets essential for neuroprotection and memory enhancing.

Topics: Animals; Calcium Channel Blockers; Dihydropyridines; Humans; Memory; Nervous System Diseases; Neuroprotection; Neurotransmitter Agents

Voltage-operated calcium channels are multimeric transmembrane proteins crucially involved in control of calcium homeostasis. Multiple types of voltage-operated calcium channels have been described in both the nervous system and peripheral tissues. Different channels can be classified according to either their biophysical properties or their pharmacology, biochemical and molecular structure, and localization and functional role. Concentrating on neuronal cells, this paper reviews the different properties of low- and high-voltage activated channels, as well as various attempts to subdivide high-voltage activated channels into different subtypes (L, N, omega, P, etc.). The availability of selective drugs (such as dihydropyridines) and natural toxins (such as omega-Conotoxin, omega-agatoxin, and funnel-web spider toxins), which bind to specific channel subtypes, has greatly helped in channel classification. The emerging view is that there are many members of the family of voltage-operated calcium channels, each with its own molecular structure, a different pharmacology, a different localization, and possibly a different physiological role. Different calcium subtypes are selectively affected in human and animal diseases. The use of omega-Conotoxin has led to identification of the channel subtype (omega) specifically affected in Lambert-Eaton myasthenic syndrome (a human disease of neurotransmission), and has permitted development of new diagnostic approaches to the disease.

Topics: Autoimmune Diseases; Calcium Channels; Dihydropyridines; Electrophysiology; Humans; Molecular Structure; Nervous System Diseases; Neurons; Toxins, Biological

Oxidative stress, inflammation and apoptotic neuronal cell death are cardinal mechanisms involved in the cascade of acute ischemic stroke. Lercanidipine apart from calcium channel blocking activity possesses anti-oxidant, anti-inflammatory and anti-apoptotic properties. In the present study, we investigated neuroprotective efficacy and therapeutic time window of lercanidipine in a 2h middle cerebral artery occlusion (MCAo) model in male Wistar rats. The study design included: acute (pre-treatment and post-treatment) and sub-acute studies. In acute studies (pre-treatment) lercanidipine (0.25, 0.5 and 1mg/kg, i.p.) was administered 60min prior MCAo. The rats were assessed 24h post-MCAo for neurological deficit score (NDS), motor deficit paradigms (grip test and rota rod) and cerebral infarction via 2,3,5-triphenyltetrazolium chloride (TTC) staining. The most effective dose was found to be at 0.5mg/kg, i.p., which was considered for further studies. Regional cerebral blood flow (rCBF) was monitored till 120min post-reperfusion to assess vasodilatory property of lercanidipine (0.5mg/kg, i.p.) administered at two different time points: 60min post-MCAo and 15min post-reperfusion. In acute studies (post-treatment) lercanidipine (0.5mg/kg, i.p.) was administered 15min, 120min and 240min post-reperfusion. Based on NDS and cerebral infarction via TTC staining assessed 24h post-MCAo, effectiveness was evident upto 120min. For sub-acute studies same dose/vehicle was repeated for next 3days and magnetic resonance imaging (MRI) was performed 96h after the last dose. Biochemical markers estimated in rat brain cortex 24h post-MCAo were oxidative stress (malondialdehyde, reduced glutathione, nitric oxide, superoxide dismutase), blood brain barrier damage (matrix metalloproteinases-2 and -9) and apoptotic (caspase-3 and -9). Lercanidipine significantly reduced NDS, motor deficits and cerebral infarction volume as compared to the control group. Lercanidipine (60min post-MCAo) significantly increased rCBF (86%) as compared to vehicle treated MCAo group (64%) 120min post-reperfusion, but failed to show vasodilatation with 15min post-reperfusion group. Lercanidipine (13.78±2.78%) significantly attenuated percentage infarct volume as evident from diffusion-weighted (DWI) and T2-weighted images as compared to vehicle treated MCAo group (25.90±2.44%) investigated 96h post-MCAo. The apparent diffusion coefficient (ADC) was also significantly improved in lercanidipine group as comp

Topics: Animals; Blood Pressure; Brain Infarction; Caspase 3; Caspase 9; Cerebrovascular Circulation; Dihydropyridines; Disease Models, Animal; Drug Administration Schedule; Gene Expression Regulation; Infarction, Middle Cerebral Artery; Laser-Doppler Flowmetry; Magnetic Resonance Imaging; Male; Matrix Metalloproteinase 2; Motor Activity; Nervous System Diseases; Neuroprotective Agents; Rats; Rats, Wistar

AE0047 [4-(4-benzhydrylpiperazino)phenethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate dihydrochloride] is a new dihydropyridine calcium antagonist with protective effects against cerebral ischaemia and the occurrence of stroke in several animal models. We investigated the effects of AE0047 on focal ischaemia induced by middle cerebral artery occlusion in stroke-prone spontaneously hypertensive rats. AE0047 at a dose causing 20 or 40% systemic hypotension (1 or 3 mg kg-1) was given orally twice, 15 min and 24 h after occlusion. The neurological status of animals was investigated 2, 24 and 48 h after occlusion. Infarct area of brain was measured 48 h after occlusion. Middle cerebral artery occlusion resulted in the progressive deterioration of neurological status and large infarction in middle cerebral artery territories with 40% mortality. AE0047 dose-dependently attenuated the deterioration of neurological status, and reduced mortality to 0 or 10%. AE0047 significantly reduced infarct size and left/right hemispheric area ratio, an index of brain swelling. These results suggest that AE0047 has the ability to ameliorate ischaemic cerebral stroke in hypertensive patients.

Topics: Animals; Blood Pressure; Brain; Calcium Channel Blockers; Cerebral Infarction; Dihydropyridines; Heart Rate; Intracranial Embolism and Thrombosis; Male; Nervous System Diseases; Rats; Rats, Inbred SHR

In the present study we investigated the effect of different Ca2+ entry blockers on the onset of neuronal damage induced by glutamate, kainate or alpha-amino-3-hydroxy-5-methyl-5-isoxazolo propionate (AMPA) in primary culture of rat cerebellar granule cells. We found that the dihydropyridine derivative, nifedipine used at 100 nM concentration, significantly counteracted the neuronal death induced by 15 min application of 50 microM glutamate. This effect was dependent on the presence of nifedipine before the exposure of granule cells to glutamate and was dose-related (IC50 = 10 nM). The nifedipine response was reproduced by isradipine and by verapamil with IC50 values of 9 and 100 nM, respectively. The activation of voltage sensitive Ca2+ channels elicited by 100 nM Bay K 8644, greatly enhanced glutamate-mediated neurotoxicity. Moreover, 100 nM isradipine was significantly active in blocking the neuronal death produced by 24 h exposure of cerebellar granule cells to 10 microM AMPA or 60 microM kainate. These results reveal a 'preventive' role of the Ca2+ entry blockers on the development of the neurodegeneration induced by overstimulation of various glutamate receptor subtypes.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Animals, Newborn; Calcium Channel Blockers; Cerebellum; Dihydropyridines; Excitatory Amino Acid Antagonists; Glutamates; Glutamic Acid; Ibotenic Acid; Isradipine; Kainic Acid; Nerve Degeneration; Nervous System Diseases; Nifedipine; Rats; Rats, Inbred Strains; Verapamil